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.

Exam domain	One-glance essentials
Definition / diagnosis	Hypothyroidism is deficiency of T3/T4 causing generalised slowing of metabolic processes ^[1] Primary disease is thyroidal; central disease arises from pituitary or hypothalamic dysfunction ^[1]
Epidemiology / risks	In Hong Kong, Hashimoto thyroiditis is the leading cause; globally, iodine deficiency remains important ^[1] Important acquired risks include thyroidectomy, radioactive iodine, neck irradiation, amiodarone, lithium and checkpoint inhibitors ^[1]
Core mechanism	Hashimoto disease causes lymphocytic thyroid destruction, often with early goitre and late atrophy ^[1] Primary disease produces high TSH; central disease produces low or inappropriately normal TSH despite low fT4 ^[1]
Clinical picture	Symptoms: cold intolerance, weight gain despite reduced appetite, fatigue, constipation, menorrhagia and cognitive slowing ^[1] Signs: bradycardia, cool coarse dry skin, non-pitting oedema and delayed-relaxation reflexes ^[1] Goitre suggests Hashimoto disease or iodine deficiency; a scar suggests post-thyroidectomy disease ^[1]
Investigations	TSH first-line: high TSH with low fT4 indicates overt primary disease; high TSH with normal fT4 indicates subclinical disease ^[1] Low or inappropriately normal TSH with low fT4 suggests central disease; check cortisol and pituitary hormones, then MRI ^[1] Anti-TPO supports Hashimoto disease; check CBC, lipids, sodium and CK for associated abnormalities ^[1] Ultrasound is for goitre or palpable nodules, not routine hypothyroidism; fT3 is usually unnecessary ^[1]
Management	Levothyroxine is replacement therapy for all causes; young healthy adults may start 1.6 mcg/kg/day ^[1] Elderly or IHD patients: start 12.5–25 mcg/day and titrate slowly; monitor TSH after 6–8 weeks ^[1] Central disease: exclude adrenal insufficiency and give hydrocortisone before or with levothyroxine ^[1] Subclinical disease: treat if TSH >10, or if symptomatic/TPOAb-positive; otherwise follow annually ^[1]
Complications	Untreated disease causes hypercholesterolaemia, atherosclerosis, pericardial or pleural effusions, anaemia and hyponatraemia ^[1] Severe disease may cause hypoventilation, hypoglycaemia, ileus, psychosis or reversible cognitive impairment ^[1] Myxoedema coma presents with hypothermia, altered consciousness, respiratory failure and cardiovascular collapse ^[1]
Prevention / follow-up	Review thyroid function after thyroidectomy, radioactive iodine or neck irradiation, and monitor patients taking amiodarone or lithium ^[1] After hemithyroidectomy, check TSH at 6 weeks; after total thyroidectomy, lifelong levothyroxine is required ^[1] Congenital disease requires universal neonatal screening and prompt treatment to prevent irreversible neurodevelopmental injury ^[1]
Exam traps	Do not treat low T3/low T4 during acute illness as hypothyroidism: consider sick euthyroid syndrome and repeat testing after recovery ^[1] A normal TSH does not exclude central disease; monitor central hypothyroidism with fT4, not TSH ^[1] Longstanding primary disease can cause thyrotroph hyperplasia mimicking a pituitary tumour; check TFTs before surgery ^[1] Never start levothyroxine before excluding adrenal insufficiency; it may precipitate adrenal crisis ^[1]

References

^[1] Senior notes: felixlai.md (Sections on Hypothyroidism: Definitions, Etiology, Classical Features)

Hypothyroidism

"Hypothyroidism" — let's break down the word: "hypo" = under/below, "thyroid" = the thyroid gland, "-ism" = a state or condition. So it literally means a state of under-functioning of the thyroid gland.

Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormones (T3 and T4), leading to a generalised slowing of metabolic processes. This deficiency may arise from disease of the thyroid gland itself (primary), from failure of the pituitary to secrete adequate TSH (secondary), or rarely from hypothalamic dysfunction (tertiary) ^[1]^[2].

Key Distinction: Hypothyroidism vs Myxoedema

Myxoedema (myxo = mucus, oedema = swelling) refers specifically to the severe form of hypothyroidism characterised by the accumulation of mucopolysaccharides (particularly hyaluronic acid) in the dermis and subcutis, causing non-pitting oedema. It is NOT synonymous with hypothyroidism — it is the end-stage clinical manifestation. Myxoedema coma is the life-threatening decompensated form.

Hypothyroidism vs Thyrotoxicosis — Get the Definitions Right

Thyrotoxicosis = the state of thyroid hormone excess (from ANY cause) ^[1]
Hyperthyroidism = excess thyroid hormone production due to excess thyroid gland function specifically ^[1]
Hypothyroidism = deficiency of thyroid hormones ^[1]
High iodine intake → associated with hyperthyroidism ^[1]
Iodine deficiency → associated with hypothyroidism ^[1]

These are NOT interchangeable. Thyrotoxicosis is broader than hyperthyroidism (e.g. exogenous T4 overdose causes thyrotoxicosis but NOT hyperthyroidism).

2. Epidemiology

Hypothyroidism is one of the most common endocrine disorders worldwide
Overt hypothyroidism: prevalence ~1–2% in women, ~0.1–0.2% in men
Subclinical hypothyroidism (elevated TSH, normal fT4): much more common, ~4–10% of the general population, increasing with age
Female:Male ratio ≈ 5–8:1 — the strong female predominance is because autoimmune diseases (the leading cause in iodine-sufficient areas) are far more common in women

Incidence increases with age — peaks in the 5th–7th decade
However, congenital hypothyroidism is an important neonatal condition (incidence ~1 in 3,000–4,000 live births)

Hong Kong is an iodine-sufficient region (due to dietary intake of seafood and iodized salt)
Therefore, the most common cause in Hong Kong is autoimmune thyroiditis (Hashimoto's thyroiditis), NOT iodine deficiency
Globally, iodine deficiency remains the most common cause of hypothyroidism (particularly in developing nations, mountainous regions)
Iatrogenic hypothyroidism is increasingly common (post-radioactive iodine therapy for Graves' disease, post-thyroidectomy for thyroid cancer or multinodular goitre) ^[2]^[3]

3. Anatomy and Function of the Thyroid Gland

The thyroid is a butterfly-shaped endocrine gland located in the anterior neck
It consists of two lateral lobes connected by an isthmus that overlies tracheal rings 2–4
A pyramidal lobe (remnant of the thyroglossal duct) may be present in ~50% of individuals, extending superiorly from the isthmus
The gland weighs approximately 15–25 g in adults
It moves with swallowing (because it is invested by the pretracheal fascia which is attached to the tracheal cartilages) — this is a key clinical sign distinguishing thyroid masses from other neck lumps ^[3]^[4]

Superior thyroid artery — first branch of the external carotid artery (supplies the upper poles)
Inferior thyroid artery — branch of the thyrocervical trunk (from the subclavian artery; supplies the lower poles and ALL FOUR parathyroid glands) ^[2]
Thyroid ima artery — present in ~3% of individuals, arises from brachiocephalic trunk or aortic arch directly
Venous drainage: superior and middle thyroid veins → internal jugular vein; inferior thyroid veins → brachiocephalic veins

Recurrent laryngeal nerve (RLN): runs in the tracheo-oesophageal groove, closely related to the inferior thyroid artery at the level of Berry's ligament. Injury → hoarseness (unilateral) or airway obstruction (bilateral, because 6 adductors > 2 abductors) ^[2]^[3]
External branch of the superior laryngeal nerve (EBSLN): runs with the superior thyroid artery near the upper pole. Injury → loss of high-pitch voice, poor volume, easy voice fatigue ^[2]

Four parathyroid glands lie posterior to the thyroid lobes
Superior parathyroids: derived from the 4th pharyngeal pouch, more constant position (shorter migration distance) ^[2]
Inferior parathyroids: derived from the 3rd pharyngeal pouch, more variable position (longer migration distance) ^[2]
ALL supplied by the inferior thyroid artery ^[2]
Damage during thyroidectomy → hypoparathyroidism → hypocalcaemia (the most common complication of total thyroidectomy, usually transient) ^[2]

The functional unit is the thyroid follicle: a sphere of follicular epithelial cells surrounding a central lumen filled with colloid (thyroglobulin-rich)
Follicular cells: produce T3 and T4
Parafollicular C cells: produce calcitonin; located in the interstitium between follicles. These are the cells of origin for medullary thyroid carcinoma ^[3]

Thyroid Hormone Physiology

Hypothalamus secretes TRH (thyrotropin-releasing hormone)
TRH stimulates the anterior pituitary (thyrotrophs) to secrete TSH (thyroid-stimulating hormone)
TSH stimulates the thyroid gland to synthesise and release T4 (thyroxine) and T3 (triiodothyronine)
T3 and T4 exert negative feedback on both the hypothalamus (↓TRH) and the pituitary (↓TSH)

This negative feedback loop is the basis of thyroid function test interpretation:

Primary hypothyroidism → low T4 → loss of negative feedback → ↑TSH (the pituitary "shouts louder")

Secondary hypothyroidism → pituitary failure → low/inappropriately normal TSH + low T4

Iodide trapping: Follicular cells actively uptake iodide from blood via the sodium-iodide symporter (NIS) on the basolateral membrane
Oxidation and organification: Iodide is oxidised by thyroid peroxidase (TPO) and incorporated into tyrosine residues on thyroglobulin → forming MIT (monoiodotyrosine) and DIT (diiodotyrosine)
Coupling: MIT + DIT → T3; DIT + DIT → T4 (still bound to thyroglobulin within colloid)
Endocytosis and proteolysis: Thyroglobulin is endocytosed back into the cell and cleaved → releasing T3 and T4 into the bloodstream
Peripheral conversion: ~80% of circulating T3 is produced by peripheral deiodination of T4 by deiodinases (mainly in the liver and kidneys). T3 is 3–5× more biologically active than T4.

Why is this important? Because drugs like amiodarone (which contains ~37% iodine by weight) and lithium interfere with these steps — amiodarone causes both thyrotoxicosis AND hypothyroidism via the Wolff-Chaikoff effect and Jod-Basedow effect, while lithium blocks thyroid hormone release ^[1].

Thyroid hormones act on virtually every tissue in the body by binding to nuclear thyroid hormone receptors, affecting gene transcription. Key effects:

System	Effect of Thyroid Hormones	Consequence of Deficiency (Hypothyroidism)
Metabolic	↑ Basal metabolic rate, ↑ O₂ consumption, ↑ heat production	Cold intolerance, weight gain, fatigue
Cardiovascular	↑ HR, ↑ contractility, ↓ SVR	Bradycardia, ↓ cardiac output, diastolic HTN
GI	↑ Gut motility	Constipation, ↓ appetite
Neurological	Required for CNS development (neonatal), ↑ synaptic transmission	Mental sluggishness, depression, cretinism (neonatal)
Musculoskeletal	Normal muscle function, bone turnover	Proximal myopathy, delayed relaxation of reflexes
Haematological	Supports erythropoiesis	Anaemia (multiple mechanisms)
Reproductive	Normal ovulatory cycles	Menorrhagia, anovulation, infertility
Dermatological	Normal skin turnover, sweat gland function	Dry, coarse skin; hair loss
Lipid metabolism	↑ LDL receptor expression → ↑ LDL clearance	Hypercholesterolaemia

4. Etiology

Classification	Causes	Pathophysiology
Primary hypothyroidism (95% of cases; problem is in the thyroid gland itself)	Iodine deficiency	Insufficient substrate for thyroid hormone synthesis. The most common cause GLOBALLY, but NOT in Hong Kong
	Autoimmune hypothyroidism
	• Hashimoto's thyroiditis (chronic lymphocytic thyroiditis)	Anti-TPO and anti-thyroglobulin antibodies → lymphocytic infiltration → gradual destruction of follicular cells → progressive hypothyroidism. Most common cause in iodine-sufficient areas (including Hong Kong)
	• Atrophic thyroiditis	TSH receptor-blocking antibodies → thyroid atrophy. Unlike Hashimoto's, NO goitre (gland atrophies instead of enlarging)
	Congenital hypothyroidism
	• Thyroid gland dysgenesis (80–85%)	Agenesis, ectopia, or hypoplasia of the thyroid gland — most commonly due to mutations in transcription factors (PAX8, TTF-1/2) ^[1]
	• Dyshormonogenesis (10–15%)	Inherited enzyme defects in thyroid hormone synthesis (e.g. TPO deficiency, Pendred syndrome = TPO + sensorineural deafness) ^[1]
	• TSH-R antibody-mediated (5%)	Maternal TSH receptor-blocking antibodies cross the placenta ^[1]
	Infiltrative hypothyroidism
	• Sarcoidosis	Granulomatous infiltration of thyroid tissue → destruction of follicles ^[1]
	• Amyloidosis	Amyloid deposition in thyroid stroma
	• Scleroderma	Fibrosis of thyroid gland
	• Riedel's thyroiditis	Dense fibrosis replacing thyroid tissue ("woody hard" thyroid) — very rare ^[1]
	Drug-induced hypothyroidism
	• Amiodarone	Contains 37% iodine by weight. The massive iodine load can cause a sustained Wolff-Chaikoff effect (excess iodine → inhibition of organification → ↓ T3/T4). Also directly toxic to thyroid cells ^[1]
	• Lithium	Inhibits thyroid hormone release and may inhibit coupling. Also promotes autoimmunity ^[1]
	• Interferon-alpha, IL-2	Can trigger autoimmune thyroiditis
	• Tyrosine kinase inhibitors (sunitinib, sorafenib)	Destructive thyroiditis; also ↑ T4 clearance
	• Immune checkpoint inhibitors (nivolumab, pembrolizumab)	Immune-related thyroiditis — increasingly common in oncology practice
	Iatrogenic hypothyroidism
	• 131-I (radioactive iodine) treatment	Radiation destroys thyroid follicular cells. Hypothyroidism is expected and often the goal of RAI treatment for Graves' disease ^[1]^[2]
	• Subtotal or total thyroidectomy	Physical removal of thyroid tissue ^[1]^[2]
	• External irradiation of neck	Radiation for head & neck cancers, lymphoma, childhood leukaemia ^[1]^[3]
Secondary hypothyroidism (Central; ~5%)	Hypothalamic disease
	• Hypothalamic tumours	Destruction of TRH-secreting neurons → ↓ TRH → ↓ TSH ^[1]
	• Trauma, infiltrative disorders
	Hypopituitarism
	• Pituitary tumour (most common cause)	Mass effect compressing thyrotrophs → ↓ TSH ^[1]
	• Pituitary surgery or irradiation	Destruction of thyrotrophs ^[1]
	• Sheehan's syndrome	Post-partum pituitary necrosis due to haemorrhagic shock — the enlarged pituitary during pregnancy is vulnerable to ischaemia ^[1]
	• Trauma, infiltrative disorders
	• Thyrotroph hyperplasia from longstanding primary hypothyroidism can enlarge the pituitary, mimicking a tumour ^[1]^[5]
Transient hypothyroidism	Subacute (De Quervain's) thyroiditis	Viral infection → granulomatous inflammation → destruction of follicles → initial thyrotoxic phase (leak of preformed hormone) → hypothyroid phase → recovery. The hypothyroid phase is typically self-limiting ^[1]
	Silent thyroiditis (including post-partum thyroiditis)	Autoimmune, painless. Same triphasic pattern as above. Post-partum thyroiditis occurs within 12 months of delivery ^[1]
	Withdrawal of supraphysiologic T4 treatment	Chronic exogenous T4 suppresses the HPT axis → abrupt withdrawal → temporary hypothyroidism until axis recovers ^[1]
	Post-131I treatment (early phase)	Thyroiditis from radiation → transient hypothyroidism before recovery or permanent damage ^[1]
	Post-subtotal thyroidectomy (early phase)	^[1]

Hong Kong Focus

In Hong Kong, the top causes to remember are:

Hashimoto's thyroiditis — the #1 cause in our iodine-sufficient population
Iatrogenic — post-thyroidectomy (very common given the surgical volume for thyroid cancer and MNG) and post-radioactive iodine for Graves' disease
Drug-induced — amiodarone (Hong Kong's ageing population with atrial fibrillation), lithium (psychiatry), immune checkpoint inhibitors (increasing use in oncology)
Post-partum thyroiditis — common and often missed

Focus on Key Aetiologies

Most important cause of hypothyroidism in iodine-sufficient areas
Named after Hakaru Hashimoto (1912) who first described lymphocytic infiltration of the thyroid
Pathophysiology: CD4+ T-helper cell mediated; anti-TPO antibodies (> 90%) and anti-thyroglobulin antibodies → complement activation, antibody-dependent cell-mediated cytotoxicity, and direct cytotoxic T cell attack on thyroid follicular cells → progressive glandular destruction
Initially may present with a goitre (due to lymphocytic infiltration and attempted compensatory growth driven by elevated TSH) → eventually atrophies in many patients
Histology: lymphocytic infiltration with germinal centre formation, Hürthle cell (oxyphilic) metaplasia, fibrosis
Associations: other autoimmune conditions (T1DM, Addison's, pernicious anaemia, vitiligo, coeliac disease) — part of autoimmune polyglandular syndromes
Association with thyroid lymphoma — Hashimoto's is a risk factor for primary thyroid lymphoma (usually MALT-type or diffuse large B-cell lymphoma) ^[3]
Risk factor for follicular carcinoma in iodine-deficient areas ^[3]

Amiodarone is a class III antiarrhythmic, very commonly used in Hong Kong
Contains ~37% iodine by weight → each 200 mg tablet delivers ~75 mg of iodine (daily requirement is only ~150 μg!)
Wolff-Chaikoff effect: the massive iodine load causes acute inhibition of TPO-mediated organification → decreased T3/T4 synthesis
In a normal thyroid, this effect is transient ("escape from Wolff-Chaikoff") → but in patients with underlying thyroid disease (e.g. subclinical Hashimoto's), the gland fails to escape → persistent hypothyroidism
AIH is more common in iodine-sufficient areas (like Hong Kong)
Distinguish from amiodarone-induced thyrotoxicosis (AIT) which is more common in iodine-deficient areas

Screened for in neonatal screening programmes (heel prick test measuring TSH) — universal screening is practised in Hong Kong
Early detection is critical because thyroid hormones are essential for CNS development in the first 2–3 years of life
Untreated → cretinism: mental retardation, short stature, puffy face, deaf mutism, protuberant abdomen, umbilical hernia ^[1]

5. Classification

Type	Site of Pathology	TSH	fT4	fT3
Primary (95%)	Thyroid gland	↑↑	↓	↓
Secondary (Central)	Pituitary	↓ or inappropriately normal	↓	↓
Tertiary (Central)	Hypothalamus	↓ or inappropriately normal	↓	↓

The distinction between secondary and tertiary is largely academic and often grouped as "central hypothyroidism." In practice, what matters is: is the TSH appropriately elevated (primary) or not (central)?

Severity	Definition	Clinical Significance
Subclinical hypothyroidism	↑ TSH + normal fT4	The thyroid is failing but compensating. TSH is working overtime to maintain fT4. Patient may be asymptomatic or have subtle symptoms. Important to decide who to treat (see Management later).
Overt (clinical) hypothyroidism	↑ TSH + ↓ fT4	Symptomatic. Requires treatment.
Myxoedema coma	Severe decompensated hypothyroidism with altered consciousness, hypothermia, cardiovascular collapse	Medical emergency. Mortality 20–60%.

Duration	Example
Transient	Subacute thyroiditis, post-partum thyroiditis, post-RAI (early), drug withdrawal
Permanent	Hashimoto's (advanced), post-total thyroidectomy, post-RAI (late), congenital dysgenesis

6. Clinical Features

The clinical features of hypothyroidism are the mirror image of thyrotoxicosis. They all stem from one core problem: generalised slowing of metabolic processes due to thyroid hormone deficiency.

Think of it this way: thyroid hormones are the body's "accelerator pedal." In hypothyroidism, you've taken your foot off the accelerator. Everything slows down — heart rate, gut motility, mental processing, metabolic rate, reflexes.

System	Symptom	Pathophysiological Basis
General	Cold intolerance	↓ BMR → ↓ thermogenesis. The body produces less heat. (Opposite of the heat intolerance in thyrotoxicosis) ^[1]
	Weight gain with loss of appetite	↓ BMR → fewer calories burned, but appetite is also reduced (paradoxical weight gain). Much of the weight gain is actually fluid retention (myxoedema) rather than fat ^[1]
	Fatigue and lethargy	↓ metabolic activity in all tissues → reduced energy production ^[1]
	Mental and physical sluggishness	↓ CNS metabolic rate → slow mentation, poor concentration, memory impairment ^[1]
Neuropsychiatric	Depression	↓ serotonin and noradrenaline turnover in CNS due to reduced metabolic activity
	Psychosis ("myxoedema madness")	Severe hypothyroidism can cause frank psychosis — always check TFTs in new-onset psychosis
	Cognitive impairment / dementia-like picture	Reversible with treatment — important DDx of "dementia" in the elderly
	Somnolence	↓ CNS arousal
Cardiovascular	Bradycardia	↓ chronotropic effect. T3 normally upregulates β1-adrenergic receptors and Na/K-ATPase in cardiomyocytes → in hypothyroidism, heart rate drops ^[1]
	Exertional dyspnoea	↓ cardiac output
GI	Constipation	↓ gut motility due to ↓ metabolic drive to smooth muscle. Can progress to ileus or even megacolon in severe cases ^[1]
	↓ Appetite	Despite weight gain
Reproductive	Menorrhagia (heavy periods)	↓ thyroid hormone → altered GnRH pulsatility → anovulatory cycles. Also ↓ levels of clotting factors. Menorrhagia can cause iron-deficiency anaemia
	Infertility, oligomenorrhoea or amenorrhoea (in severe cases)	↑ TRH → ↑ prolactin (TRH stimulates prolactin release) → suppresses GnRH → hypogonadotrophic hypogonadism
	↓ Libido, erectile dysfunction	↑ prolactin effect + general metabolic slowing
Musculoskeletal	Muscle aches, cramps, stiffness	Accumulation of glycosaminoglycans in muscle, ↓ muscle metabolism
	Proximal myopathy	↓ oxidative metabolism in muscle → weakness (test by asking patient to raise arms above head or stand from squatting) ^[1]
Skin/Hair	Dry, coarse skin	↓ sweat and sebaceous gland activity
	Hair loss (diffuse alopecia)	↓ hair follicle cycling
	Brittle nails	↓ nail matrix activity
Voice	Hoarse, deep voice	Myxoedematous infiltration of vocal cords and laryngeal mucosa ^[1]

The Paradox of Weight Gain with Loss of Appetite

Students often ask: "How can you gain weight if you're eating less?" The answer is that the reduction in metabolic rate is proportionally greater than the reduction in caloric intake. Also, much of the "weight gain" is water and glycosaminoglycan accumulation (myxoedema) rather than true adipose tissue gain ^[1].

Location	Sign	Pathophysiological Basis
General	Slow, nasal, and deep voice	Myxoedematous thickening of vocal cords and pharyngeal/nasal mucosa ^[1]
	Hypothermia	↓ thermogenesis
	Obesity/overweight	↓ BMR
Hands	Peripheral cyanosis	↓ cardiac output → poor peripheral perfusion → deoxygenation of peripheral blood ^[1]
	Palmar crease pallor	Anaemia — this is multifactorial ^[1]:
		1. Anaemia of chronic disease (most common) — cytokine-mediated ↓ erythropoiesis
		2. Iron deficiency anaemia — from menorrhagia
		3. Folate deficiency anaemia — from bacterial overgrowth (↓ gut motility → stasis → bacterial overgrowth → folate consumption)
		4. Pernicious anaemia — from associated autoimmune gastritis (anti-intrinsic factor antibodies)
	Dry and cool skin	↓ sweat gland activity (cool) + ↓ sebaceous activity (dry) ^[1]
	Yellow discoloration (carotenodermia)	Hypercarotenaemia — hepatic metabolism of carotene is slowed down in hypothyroidism → carotene accumulates in the skin ^[1]. Note: this is NOT jaundice (sclerae are NOT yellow in carotenodermia)
	Abnormal pulse — small volume, bradycardic	↓ stroke volume + ↓ heart rate ^[1]
	Carpal tunnel syndrome	Sensory loss as the carpal tunnel is thickened in myxoedema — glycosaminoglycan deposition in the transverse carpal ligament and surrounding tissues compresses the median nerve ^[1]
	Doughy, thickened skin	Mucopolysaccharide deposition in dermis
Arms	Proximal myopathy	Test by raising arms above the head ^[1] — weakness of shoulder girdle muscles due to ↓ oxidative metabolism
	"Hung-up" biceps reflex	Delayed relaxation phase of deep tendon reflexes — the muscle contracts normally but the relaxation (which depends on ATP-dependent calcium reuptake into the sarcoplasmic reticulum) is slowed because metabolic processes are slowed ^[1]
Legs	Non-pitting oedema (myxoedema)	Accumulation of hyaluronic acid and other glycosaminoglycans in the dermis and subcutis → these attract water by osmosis → but the water is trapped within a gel-like matrix, so the oedema does NOT pit on pressure ^[1]
	"Hung-up" Achilles reflex	Rapid dorsiflexion followed by slow plantar flexion after the tendon is tapped — same mechanism as above (delayed relaxation). This is a very specific sign of hypothyroidism ^[1]
	Pretibial myxoedema (non-pitting)	Same mechanism — note: pretibial myxoedema is classically associated with Graves' disease (an autoimmune phenomenon), but non-pitting oedema in hypothyroidism from ANY cause occurs due to GAG deposition
Eyes	Periorbital oedema	Myxoedematous infiltration of periorbital tissues ^[1]
	Loss or thinning of outer third of eyebrows ("Queen Anne sign" / "Hertoghe sign")	Unknown exact mechanism, but believed to be due to ↓ hair follicle metabolism in this region ^[1]
	Xanthelasmata	Due to associated hypercholesterolaemia — thyroid hormones normally upregulate hepatic LDL receptors. In hypothyroidism, LDL clearance ↓ → LDL accumulates → cholesterol deposits around the eyes ^[1]
Neck	Goitre	Compensatory over-secretion of TSH — in primary hypothyroidism, low T4 → ↑ TSH → TSH stimulates thyroid growth → goitre. Note: NOT all causes of hypothyroidism cause goitre (e.g. atrophic thyroiditis causes gland shrinkage, post-thyroidectomy obviously has no gland) ^[1]
	Thyroidectomy scar	Assess for iatrogenic hypothyroidism (and also assess for hypoparathyroidism) ^[1]^[2]
Chest	Pericardial effusion	↑ capillary permeability + ↓ lymphatic drainage + GAG deposition → fluid accumulation in pericardial space. Usually slow-accumulating → rarely causes tamponade ^[1]
	Pleural effusion	Same mechanism as pericardial effusion ^[1]
Skin (general)	Myxoedema — pink, brown, or skin-coloured non-pitting oedema	Hyaluronic acid accumulates in dermis and subcutis ^[1]
	Dry, coarse, flaky skin	↓ sweat and sebaceous gland function
	Sparse, coarse hair	↓ follicular activity
	Periorbital puffiness	GAG deposition
Newborn	Cretinism features	Short stature, mental retardation, puffy face, deaf mutism, protuberant abdomen, umbilical hernia — T3/T4 are essential for CNS myelination and skeletal maturation in the first 2–3 years of life; deficiency causes irreversible damage ^[1]

Hung-up Reflexes — Why?

The delayed relaxation phase is one of the most specific signs of hypothyroidism. Here's the mechanism:

Muscle relaxation requires calcium reuptake back into the sarcoplasmic reticulum via SERCA (sarco/endoplasmic reticulum Ca²⁺-ATPase). This pump is ATP-dependent. In hypothyroidism, ↓ metabolic rate → ↓ ATP production → ↓ SERCA activity → calcium stays in the cytoplasm longer → the muscle stays contracted longer → delayed relaxation.

The Achilles tendon reflex (ankle jerk) is the easiest to assess: you tap the tendon, the foot dorsiflexes briskly (normal contraction phase), but then the foot descends back very slowly (delayed relaxation phase).

Why Does Hypothyroidism Cause Hypercholesterolaemia?

Thyroid hormones (especially T3) upregulate the expression of hepatic LDL receptors. When T3 is deficient:

↓ LDL receptors on hepatocytes
↓ Clearance of LDL-cholesterol from the blood
→ ↑ Total cholesterol and ↑ LDL-cholesterol

This is clinically significant because:

It causes xanthelasmata (cholesterol deposits around the eyes)
It is an accelerated atherosclerosis risk factor
It should be corrected by treating the hypothyroidism before starting a statin — always check TFTs in a patient with new-onset dyslipidaemia!

Distinguishing Causes by Goitre Presence

Hypothyroidism WITH goitre	Hypothyroidism WITHOUT goitre
Hashimoto's thyroiditis (early)	Atrophic thyroiditis
Iodine deficiency	Post-thyroidectomy
Dyshormonogenesis	Post-radioactive iodine
Drug-induced (lithium, amiodarone)	Pituitary/hypothalamic disease
Infiltrative (Riedel's)	Late-stage Hashimoto's (burnt out)

The presence or absence of a goitre helps narrow the differential.

Special Clinical Scenarios

↑ TSH + normal fT4
Patient may be completely asymptomatic or have very subtle symptoms (mild fatigue, slight weight gain)
Important because:
- ~2–5% per year progress to overt hypothyroidism (higher if anti-TPO antibodies positive)
- Associated with adverse cardiovascular outcomes (dyslipidaemia, endothelial dysfunction)
- Treatment decision depends on TSH level, symptoms, age, and antibody status (discussed in Management)

Untreated maternal hypothyroidism is associated with:
- Pre-eclampsia, placental abruption, post-partum haemorrhage
- Impaired fetal neurocognitive development (IQ reduction)
- Miscarriage, preterm delivery
TSH targets in pregnancy are trimester-specific (generally lower than non-pregnant reference ranges)

The most severe, life-threatening manifestation
Precipitants: cold exposure, infection, sedatives, surgery, non-compliance with thyroxine
Features: hypothermia, altered consciousness/coma, bradycardia, hypotension, hypoventilation, hyponatraemia (↓ free water clearance due to ↑ ADH)
Mortality 20–60% even with treatment

High Yield Summary

Definition: Hypothyroidism = deficiency of thyroid hormones (T3/T4) → generalised metabolic slowing.

Key Distinctions: Primary (95%; thyroid gland problem, ↑TSH) vs Central/Secondary (5%; pituitary/hypothalamic, low/normal TSH). Subclinical (↑TSH, normal fT4) vs Overt (↑TSH, ↓fT4).

Most common cause globally: Iodine deficiency. In Hong Kong: Hashimoto's thyroiditis (autoimmune).

Hashimoto's: Anti-TPO + anti-Tg antibodies → lymphocytic destruction → goitre (early) → atrophy (late). Associated with other autoimmune diseases and thyroid lymphoma.

Drug causes: Amiodarone (Wolff-Chaikoff effect), Lithium (blocks release), Checkpoint inhibitors (immune thyroiditis).

Iatrogenic: Post-thyroidectomy, post-RAI, post-external neck irradiation — very common in HK.

Cardinal symptoms: Cold intolerance, weight gain (with ↓ appetite), fatigue, constipation, menorrhagia, mental sluggishness, hoarse voice, dry skin.

Cardinal signs: Bradycardia, non-pitting oedema (myxoedema), hung-up reflexes (delayed relaxation), periorbital oedema, thinning of outer 1/3 eyebrows, yellow skin (carotenodermia NOT jaundice), carpal tunnel syndrome, goitre (if primary with intact gland), dry/cool/coarse skin.

Anaemia in hypothyroidism is multifactorial: ACD, iron deficiency (menorrhagia), folate deficiency (bacterial overgrowth), pernicious anaemia (autoimmune association).

Hypercholesterolaemia: ↓ LDL receptors → ↓ LDL clearance → ↑ cholesterol → xanthelasmata, accelerated atherosclerosis. Always check TFTs before starting a statin for new dyslipidaemia.

Myxoedema coma: Most severe form. Hypothermia + altered consciousness + cardiovascular collapse. Medical emergency.

Congenital hypothyroidism: Universal neonatal screening (HK). Untreated → cretinism (irreversible mental retardation, short stature, deaf mutism).

Active Recall - Hypothyroidism: Definition, Epidemiology, Etiology and Clinical Features

^[1] Senior notes: felixlai.md (Sections on Hypothyroidism: Definitions, Etiology, Classical Features) ^[2] Senior notes: maxim.md (Sections on Thyroid surgery complications, Thyroid anatomy, Parathyroid) ^[3] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf ^[4] Lecture slides: GC 218. I have a swelling in the neck Neck mass (Notes).pdf ^[5] Senior notes: felixlai.md (Pituitary adenomas and sellar masses section)

Differential Diagnosis of Hypothyroidism

When a patient presents with features suggestive of hypothyroidism — fatigue, weight gain, cold intolerance, constipation, dry skin, bradycardia — your job is twofold:

Confirm that hypothyroidism is the diagnosis (as opposed to mimics that share overlapping features)
Determine the cause of the hypothyroidism (because management differs)

Let's tackle both systematically.

Many conditions share individual features with hypothyroidism. The key is that hypothyroidism produces a constellation of symptoms across multiple systems simultaneously — if only one or two features are present, think of the alternatives below.

Clinical Feature	Hypothyroidism Mimic	How to Distinguish
Fatigue + weight gain	Depression	Depression has anhedonia, low mood, sleep disturbance. TFTs normal. Note: hypothyroidism itself causes depression — always check TFTs in new-onset depression ^[1]
	Chronic fatigue syndrome	No objective metabolic signs (normal reflexes, normal HR, normal skin). TFTs normal
	Cushing's syndrome	Central obesity, moon face, striae, buffalo hump, hyperglycaemia. Cortisol elevated. Different fat distribution pattern (central vs diffuse in hypothyroidism)
	Obstructive sleep apnoea	Daytime somnolence, snoring, obesity. Sleep study diagnostic
Constipation	IBS (constipation-predominant)	Fluctuating symptoms, meets Rome IV criteria, TFTs normal ^[6]
	Drug-induced (opioids, CCBs)	Temporal relationship with drug. TFTs normal ^[6]
	Hypercalcaemia	Check serum calcium — hyperparathyroidism can coexist with hypothyroidism (autoimmune polyglandular syndrome or post-thyroidectomy hypocalcaemia is the opposite!)
	Hypokalemia	Check electrolytes ^[6]
	Colonic malignancy	Red flags: PR bleeding, weight loss, iron deficiency anaemia. Colonoscopy
Bradycardia	Beta-blocker use	Drug history
	Sick sinus syndrome	ECG, Holter monitor
	Raised intracranial pressure	Cushing's reflex (bradycardia + hypertension + irregular breathing). Neurological signs
Dry skin / hair loss	Iron deficiency anaemia	Check ferritin, iron studies
	Dermatological conditions (eczema, psoriasis)	Localised vs generalised, no metabolic features
	Ageing	No goitre, normal TFTs
Non-pitting oedema	Lymphoedema	Usually unilateral or asymmetric, history of surgery/radiation/infection
	Pretibial myxoedema of Graves' disease	Paradoxically in hyperthyroidism — autoimmune GAG deposition (TSH receptor antibodies on dermal fibroblasts). Bilateral shins, "peau d'orange" appearance
Periorbital oedema	Nephrotic syndrome	Heavy proteinuria, hypoalbuminaemia, generalised pitting oedema
	Allergic/angioedema	Acute onset, urticaria, history of allergen exposure
Carpal tunnel syndrome	Primary CTS (most common)	Ageing, female, DM, hypothyroid, RA, obesity, pregnancy are all risk factors ^[7]. Always check TFTs in new CTS — hypothyroidism is a treatable secondary cause
	Cervical radiculopathy (C6/7)	Neck pain, dermatomal distribution, neck movement exacerbates ^[7]
Hoarse voice	Laryngeal pathology	Direct laryngoscopy. RLN palsy from other causes (lung cancer, post-thyroidectomy) ^[2]
	GORD (laryngopharyngeal reflux)	Heartburn, throat clearing
Hypercholesterolaemia	Familial hypercholesterolaemia	Family history, tendon xanthomata, very high LDL. TFTs normal — but always check TFTs before starting a statin for new dyslipidaemia
	Nephrotic syndrome	Proteinuria, hypoalbuminaemia
Effusions (pericardial/pleural)	Heart failure	Elevated BNP, cardiomegaly, other signs of HF
	Malignancy	Bloody effusion, cytology positive
	Infection (TB in Hong Kong)	Fever, lymphocytic exudate
Cognitive decline	Dementia (Alzheimer's, vascular)	Hypothyroidism is a reversible cause of dementia — always check TFTs in cognitive decline workup. If TFTs abnormal, treat first and reassess
Goitre	See Section B below	Goitre has its own extensive DDx
Mental sluggishness / "slow"	Normal ageing	No objective signs. TFTs normal
	Medications (sedatives, anticonvulsants)	Drug history
Galactorrhoea	Prolactinoma	Hypothyroidism causes ↑ TRH → ↑ prolactin → galactorrhoea. Must check TFTs AND prolactin. If TFTs show hypothyroidism, treat it — prolactin often normalises ^[8]
	Drug-induced (antipsychotics, metoclopramide, domperidone)	Temporal relationship with drug ^[8]

The 'Check TFTs' Rule

In clinical practice, TFTs should be checked in ANY patient presenting with:

New-onset depression or cognitive decline
Unexplained weight gain
New-onset constipation without obvious cause
New dyslipidaemia (before starting a statin!)
New carpal tunnel syndrome
Unexplained effusions
Galactorrhoea / menstrual irregularities
Unexplained anaemia

Hypothyroidism is common, easily diagnosed, and easily treated — missing it is unforgivable.

B. Differential Diagnosis of the Cause of Hypothyroidism

Once hypothyroidism is confirmed biochemically (↑ TSH + ↓ fT4 = primary; low/normal TSH + ↓ fT4 = central), you must determine the aetiology. The approach is systematic:

Feature	Primary Hypothyroidism	Central (Secondary/Tertiary) Hypothyroidism
TSH	↑↑ (the pituitary "shouts louder" because it senses low T4)	Low or inappropriately normal (the pituitary is broken — it can't respond)
fT4	↓	↓
Goitre	May be present (Hashimoto's, iodine deficiency, drug-induced)	Absent (no TSH drive to enlarge gland)
Other pituitary hormone deficiency	No	Yes — look for hypocortisolism, hypogonadism, GH deficiency (panhypopituitarism)
Prevalence	~95% of all hypothyroidism	~5%

Why does this distinction matter? Because in central hypothyroidism, you must exclude coexisting adrenal insufficiency BEFORE starting thyroxine. Starting T4 in a patient with undiagnosed adrenal insufficiency increases cortisol metabolism → precipitates acute adrenal crisis (Addisonian crisis) → potentially fatal ^[1].

The differential of primary hypothyroidism is essentially the aetiological table from the previous section. Clinically, you narrow it down using:

Clue	Points Towards
Goitre present	Hashimoto's (early), iodine deficiency, dyshormonogenesis, drug-induced (lithium, amiodarone), Riedel's thyroiditis
No goitre	Atrophic thyroiditis, post-thyroidectomy, post-RAI, post-external radiation, late Hashimoto's (burnt out)
Thyroidectomy scar on neck	Iatrogenic — post-thyroidectomy ^[1]. Also assess for hypoparathyroidism (hypocalcaemia) ^[2]
History of RAI treatment	Post-RAI hypothyroidism (expected outcome of Graves' treatment) ^[1]
Drug history: amiodarone, lithium, checkpoint inhibitors, interferon	Drug-induced hypothyroidism ^[1]
Anti-TPO and/or anti-Tg antibodies positive	Autoimmune — Hashimoto's (anti-TPO 90–100%, anti-Tg 80–90%) or atrophic thyroiditis ^[1]
Previous neck irradiation (e.g. childhood leukaemia, lymphoma)	Radiation-induced thyroid failure ^[3]^[4]
Post-partum (within 12 months of delivery)	Post-partum thyroiditis (transient; may follow a thyrotoxic phase) ^[1]
Painful, tender thyroid + preceding URTI	Subacute (De Quervain's) thyroiditis — transient hypothyroid phase ^[1]
Neck irradiation + enlarged pituitary	Could be radiation to hypothalamus/pituitary → central hypothyroidism. Also, longstanding primary hypothyroidism → thyrotroph hyperplasia mimicking a pituitary tumour ^[5]
Other autoimmune conditions (T1DM, Addison's, vitiligo, pernicious anaemia)	Autoimmune polyglandular syndrome — Hashimoto's is the likely thyroid cause
Newborn with screening TSH elevated	Congenital hypothyroidism — thyroid dysgenesis (80–85%), dyshormonogenesis (10–15%), maternal blocking antibodies (5%) ^[1]
Family history of MEN II	Post-thyroidectomy for medullary thyroid carcinoma ^[3]^[4]
Woody hard, fixed thyroid	Riedel's thyroiditis (very rare) ^[1]

Clue	Points Towards
Headache, visual field defects (bitemporal hemianopia)	Pituitary macroadenoma compressing optic chiasm ^[5]
Other pituitary hormone deficiency (amenorrhoea, ↓ libido, fatigue, hypoglycaemia)	Panhypopituitarism — tumour, surgery, irradiation, infiltrative ^[5]
Post-partum haemorrhage, failure to lactate	Sheehan's syndrome — post-partum pituitary necrosis ^[1]^[5]
History of pituitary surgery or cranial irradiation	Iatrogenic hypopituitarism ^[5]
History of head trauma	Traumatic hypopituitarism
Diabetes insipidus features (polyuria, polydipsia)	Hypothalamic/posterior pituitary disease

Pituitary Enlargement in Primary Hypothyroidism — A Trap!

Longstanding untreated primary hypothyroidism → chronically elevated TSH → thyrotroph hyperplasia → the pituitary gland enlarges and can mimic a pituitary adenoma on MRI ^[5]. This is important because:

You might misdiagnose it as a pituitary tumour and operate unnecessarily
The "tumour" shrinks with thyroid hormone replacement — always check TFTs before pituitary surgery for an apparently non-functioning adenoma!

Since many patients with hypothyroidism present with a goitre (or conversely, a goitre is discovered and TFTs reveal hypothyroidism), you must know the differential diagnosis of goitre and how it maps to thyroid function status.

Classification of goitre ^[3]:

Category	Examples	Thyroid Status
Simple goitre (endemic or sporadic)	Diffuse or nodular	Euthyroid (or mildly hypothyroid if iodine deficiency)
Neoplastic goitre	Benign (follicular adenoma) or Malignant (papillary, follicular, anaplastic, medullary CA) ^[3]^[4]	Usually euthyroid (rarely thyrotoxic — functioning adenoma, metastatic thyroid CA)
Thyroiditis	Bacterial (acute suppurative), viral (subacute/De Quervain's), lymphocytic/Hashimoto/autoimmune (chronic) ^[3]	Variable — thyrotoxic (early destructive), hypothyroid (late), or euthyroid
Toxic goitre	Diffuse toxic (Graves'), toxic nodular (Plummer's), toxic/functioning adenoma ^[3]	Thyrotoxic

Approach to thyroid nodules ^[4]:

Pattern	Differential
Solitary nodule	Dominant nodule in MNG; Cyst (true simple cyst, colloid nodule); Neoplastic (adenoma, toxic adenoma, carcinoma) ^[4]
Multiple nodules	MNG (hyperplastic/adenomatous nodules with varying degree of cystic degeneration); toxic MNG; multiple cysts; multiple adenoma ^[4]
Diffuse	Graves' disease; Physiological (pregnancy, puberty); Hashimoto's thyroiditis; De Quervain's/subacute thyroiditis ^[4]

Thyroid nodule pathology ^[3]:

Nodular goitre: colloid / haemorrhagic cystic / complex / hyperplastic / adenomatous nodule (70%)
Benign follicular adenoma: mainly non-toxic (15%)
Well-differentiated thyroid carcinoma (10%)
Miscellaneous: other thyroid malignancies, thyroiditis (5%)

Around 10–15% of nodules are malignant ^[4] — this is why ALL thyroid nodules need proper workup even if the patient is hypothyroid.

Hypothyroid + Goitre = Think Hashimoto's First (in HK)

In a Hong Kong patient with hypothyroidism AND a goitre, Hashimoto's thyroiditis is the #1 diagnosis. Confirm with anti-TPO antibodies (positive in 90–100%) ^[1]. The goitre in Hashimoto's is typically diffusely enlarged, firm, rubbery, and may have a bosselated (irregular/lobulated) surface. However, always exclude coexisting thyroid nodules/malignancy — Hashimoto's is a risk factor for thyroid lymphoma ^[4].

This is the most practical approach in clinical practice. You get the TFTs back — now what?

TFT Pattern	TSH	fT4	fT3	Diagnosis	Next Step
Primary overt hypothyroidism	↑↑	↓	↓	Primary hypothyroidism	Check anti-TPO, anti-Tg. Review drug history, surgical history, RAI history
Subclinical hypothyroidism	↑ (mildly)	Normal	Normal	Mild/subclinical hypothyroidism	Check anti-TPO → if positive AND symptomatic → treat. If negative and asymptomatic → annual follow-up ^[1]
Central hypothyroidism	Low or inappropriately normal	↓	↓	Pituitary/hypothalamic disease	MRI pituitary, anterior pituitary hormone panel (cortisol FIRST — exclude adrenal insufficiency before starting T4)
Low T4, low TSH, low T3 (acutely unwell patient)	Low	Low	Low	Sick euthyroid syndrome (non-thyroidal illness syndrome)	Do NOT treat with thyroxine. Repeat TFTs after recovery. The low T3 is an adaptive response to severe illness (reduces metabolic demand)
High TSH, normal fT4, normal fT3 (with high anti-TPO)	↑	Normal	Normal	Early Hashimoto's / subclinical hypothyroidism	Monitor or treat depending on TSH level and symptoms ^[1]

Sick Euthyroid Syndrome — Don't Be Fooled!

In any acutely unwell patient (ICU, sepsis, post-surgery, acute MI), TFTs can be misleading:

T3 drops first (↓ peripheral conversion of T4 → T3 as an adaptive mechanism to reduce metabolic demand)
T4 may also drop
TSH can be low, normal, or transiently elevated during recovery

This does NOT mean the patient is hypothyroid. Do NOT start thyroxine. Repeat TFTs 6–8 weeks after recovery. Treating sick euthyroid syndrome with thyroxine may actually be harmful (increases catabolism in an already stressed patient).

This flowchart is adapted from the diagnostic algorithm in the senior notes ^[1] and reflects the standard clinical approach.

Hypothyroidism Causing Other Conditions (Don't Forget the Reverse)

Hypothyroidism itself can be the underlying cause of other presentations. Always consider hypothyroidism in the DDx of:

Presentation	Why Hypothyroidism Causes It
Constipation	↓ gut motility → also consider in DDx of pseudo-obstruction (metabolic: hypothyroidism) ^[6]
Carpal tunnel syndrome	GAG deposition thickens the transverse carpal ligament → median nerve compression. Hypothyroid is listed as a secondary cause of CTS ^[7]
Paralytic ileus / pseudo-obstruction	Hypothyroidism is listed as a metabolic cause of both paralytic ileus and pseudo-obstruction ^[6]
Galactorrhoea	↑ TRH → ↑ prolactin → milky nipple discharge ^[8]
Hypercholesterolaemia	↓ LDL receptors. Always check TFTs before diagnosing primary dyslipidaemia
Pericardial / pleural effusion	↑ capillary permeability + GAG deposition
Anaemia (macrocytic or normocytic)	Multiple mechanisms (ACD, B12/folate deficiency, iron deficiency from menorrhagia) ^[1]
Hyponatraemia	↑ ADH secretion (inappropriate) + ↓ free water clearance + ↓ cardiac output → dilutional hyponatraemia
Elevated CK	Myopathy → CK leak. Can be misdiagnosed as myocardial infarction or rhabdomyolysis
Gynaecomastia	Altered oestrogen:androgen ratio from hypothyroidism-associated hypogonadism ^[9]
Pituitary enlargement (pseudo-tumour)	Thyrotroph hyperplasia from longstanding primary hypothyroidism ^[5]

Key Exam Point: The differential diagnosis of hypothyroidism is really three questions in one:

Is it truly hypothyroidism or a mimic? → Confirm with TFTs

Is it primary or central? → TSH tells you

What is the specific cause? → Clinical context (antibodies, history, drugs, surgery) tells you

High Yield Summary

Mimics of hypothyroidism: Depression, chronic fatigue syndrome, Cushing's, OSA, nephrotic syndrome, normal ageing — all share individual features but lack the full metabolic constellation. TFTs distinguish.

Primary vs Central: TSH is the key — elevated = primary (95%), low/normal = central (5%). In central, ALWAYS exclude adrenal insufficiency before starting T4.

Sick euthyroid syndrome: Low T3 ± low T4 ± low TSH in acutely unwell patients. Do NOT treat with thyroxine. Repeat TFTs after recovery.

Most common cause in HK: Hashimoto's (anti-TPO 90–100%). Drug-induced (amiodarone, lithium, checkpoint inhibitors) and iatrogenic (post-thyroidectomy, post-RAI) are also very common.

Goitre DDx maps to thyroid status: Euthyroid (simple goitre, adenoma), hypothyroid (Hashimoto's, iodine deficiency), hyperthyroid (Graves', toxic MNG, toxic adenoma). Around 10–15% of thyroid nodules are malignant.

Thyrotroph hyperplasia trap: Longstanding primary hypothyroidism → pituitary enlargement mimicking adenoma. Shrinks with T4 replacement — check TFTs before pituitary surgery.

Always check TFTs in: new depression, new CTS, new dyslipidaemia, new constipation, cognitive decline, galactorrhoea, unexplained effusions, unexplained anaemia, pseudo-obstruction.

Active Recall - Differential Diagnosis of Hypothyroidism

References

^[1] Senior notes: felixlai.md (Hypothyroidism: Definitions, Etiology, Diagnosis, Clinical Features, Treatment) ^[2] Senior notes: maxim.md (Thyroid surgery complications, Parathyroid anatomy) ^[3] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (Goitre classification, Thyroid nodule pathology) ^[4] Senior notes: maxim.md (Approach to thyroid nodules, Thyroid cancer overview, Risk factors) ^[5] Senior notes: felixlai.md (Pituitary adenomas, Differential diagnosis of sellar mass, Thyrotroph hyperplasia) ^[6] Senior notes: maxim.md (Constipation DDx, Paralytic ileus, Pseudo-obstruction aetiology) ^[7] Senior notes: maxim.md (Carpal tunnel syndrome risk factors and clinical features) ^[8] Senior notes: felixlai.md (Nipple discharge and galactorrhoea, Hypothyroidism causing hyperprolactinaemia) ^[9] Senior notes: maxim.md (Gynaecomastia aetiology)

Diagnostic Criteria, Algorithm, and Investigations for Hypothyroidism

A. Diagnostic Criteria — First Principles

Unlike many conditions that have formal "diagnostic criteria" (e.g. the Jones criteria for rheumatic fever), hypothyroidism is diagnosed biochemically. The clinical features are supportive but non-specific — many conditions mimic hypothyroidism. The diagnosis rests on thyroid function tests (TFTs).

Let's build the diagnostic logic from first principles of the HPT axis:

TSH is the gatekeeper. The anterior pituitary is exquisitely sensitive to circulating T4/T3 levels. Even tiny drops in free T4 cause a disproportionately large rise in TSH (logarithmic-linear relationship). This is why TSH is the MOST sensitive indicator of thyroid function due to its short half-life — it changes dynamically in response to alterations in T3 and T4 ^[1].
fT4 determines severity. Once TSH is elevated, measuring fT4 tells you whether the patient has:
- Subclinical hypothyroidism (↑ TSH, normal fT4) — the thyroid is struggling but compensating
- Overt hypothyroidism (↑ TSH, ↓ fT4) — the thyroid has failed
Anti-TPO antibodies determine aetiology. If positive → autoimmune (Hashimoto's or atrophic thyroiditis). If negative → look for other causes (iatrogenic, drug-induced, etc.)

Diagnosis	TSH	fT4	fT3	Notes
Primary overt hypothyroidism	↑↑	↓	↓ (or normal)	fT3 level is NOT needed since it can be normal (not necessarily low) in 25% of patients due to peripheral conversion from T4 → T3 by adaptive deiodinase responses to hypothyroidism ^[1]
Subclinical (mild) hypothyroidism	↑ (mildly, typically 4.5–10 mU/L)	Normal	Normal	The gland is compensating. TSH is working overtime to maintain fT4.
Central (secondary/tertiary) hypothyroidism	Low or inappropriately normal	↓	↓	The pituitary is broken — it cannot mount an appropriate TSH response. TSH may even be "normal" numerically but is inappropriate for the low fT4

Why Measure fT4 and NOT Total T4?

T3 and T4 are highly protein-bound and many factors influence protein binding ^[1]:

Thyroxine-binding globulin (TBG) carries ~70% of circulating T4
Total T3 or T4 are elevated when TBG is increased: pregnancy, oral contraceptives, hormonal therapy ^[1]
Total T3 or T4 are reduced when TBG is decreased: androgens, hypoalbuminaemia ^[1]
fT3 and fT4 are normal in euthyroid patients with the above circumstances and hence are preferable over total thyroid hormones ^[1]

So measuring total T4 would give you falsely high values in pregnant women on OCPs and falsely low values in nephrotic syndrome — leading to misdiagnosis. Free T4 (fT4) measures only the biologically active, unbound fraction and is unaffected by binding protein changes.

TSH Limitations — When It Misleads You

TSH should NOT be used as an isolated test in patients with suspected or known pituitary disease ^[1]. Key caveats:

↑ TSH alone may not necessarily indicate hypothyroidism — e.g. recovery phase of sick euthyroid syndrome (TSH transiently rises), TSH-secreting pituitary adenoma (secondary hyperthyroidism) ^[1]
↓ TSH alone may not necessarily indicate hyperthyroidism — e.g. central (secondary) hypothyroidism, 1st trimester of pregnancy (due to hCG secretion which stimulates TSH receptor by molecular mimicry), high dose glucocorticoids or dopamine (suppress TSH secretion) ^[1]

Bottom line: TSH is the best first-line test for PRIMARY thyroid disease. But if you suspect pituitary/hypothalamic disease, you MUST measure fT4 alongside TSH.

The following algorithm is adapted directly from the senior notes ^[1] and reflects the standard clinical approach to evaluating hypothyroidism.

Step-by-Step Walkthrough

Step 1: Measure TSH — This is your screening test. It is the single most useful test.

Step 2: Interpret the TSH

If elevated → the pituitary is "shouting" because it senses low thyroid hormones → likely primary hypothyroidism → proceed to measure fT4
If normal → ask yourself: is there clinical suspicion of pituitary disease? If no → no further tests. If yes → measure fT4 anyway (because TSH can be inappropriately normal in central hypothyroidism)

Step 3: Measure fT4

If TSH elevated + fT4 low → Primary overt hypothyroidism → check anti-TPO antibodies to determine aetiology
If TSH elevated + fT4 normal → Subclinical (mild) hypothyroidism → check anti-TPO antibodies to guide management
If TSH normal/low + fT4 low (with clinical suspicion of pituitary disease) → Rule out drug effects, sick euthyroid syndrome, then evaluate anterior pituitary function ^[1]

Step 4: Anti-TPO Antibodies

If TPOAb+ → autoimmune hypothyroidism → T4 treatment ^[1]
If TPOAb- → rule out other causes of hypothyroidism → T4 treatment ^[1]
For subclinical hypothyroidism: if TPOAb+ or symptomatic → T4 treatment. If TPOAb-, no symptoms → annual follow-up ^[1]

The Algorithm in One Sentence

TSH first → if elevated, fT4 next → if low, it's overt primary hypothyroidism; if normal, it's subclinical → then TPO antibodies to determine cause and guide treatment. If TSH is normal/low but you suspect pituitary disease, measure fT4 anyway.

C. Investigation Modalities — Detailed Breakdown

Let's go through each investigation systematically, explaining what it is, why we do it, key findings, and interpretation.

1. Thyroid Function Tests (TFTs)

These are the cornerstone of diagnosis.

Aspect	Detail
What it measures	Concentration of thyroid-stimulating hormone from the anterior pituitary
Why it's the best first test	TSH is the MOST sensitive indicator of thyroid function due to the logarithmic-linear relationship: small changes in fT4 cause large reciprocal changes in TSH ^[1]
Normal range	~0.4–4.0 mU/L (varies by assay and population; may be higher in elderly)
In primary hypothyroidism	↑↑ — often > 10 mU/L in overt disease
In subclinical hypothyroidism	Mildly ↑ — typically 4.5–10 mU/L
In central hypothyroidism	Low or inappropriately normal
Monitoring caveat	Do NOT use TSH level to monitor response to treatment since it can remain suppressed for several months (in patients transitioning from hyperthyroid to hypothyroid states, or early in T4 replacement) — use T3 and T4 level instead initially ^[1]

Aspect	Detail
What it measures	Unbound, biologically active T4 in serum
Why fT4 and not total T4	Unaffected by changes in binding proteins (pregnancy ↑ TBG, nephrotic syndrome ↓ TBG, OCP ↑ TBG) ^[1]
In primary overt hypothyroidism	↓
In subclinical hypothyroidism	Normal (the gland is compensating under TSH drive)
Key point	fT4 level is required to determine subclinical or overt hypothyroidism ^[1]

Aspect	Detail
Role in hypothyroidism	fT3 level is NOT needed in the evaluation of hypothyroidism ^[1]
Why?	fT3 can be normal in 25% of hypothyroid patients due to peripheral conversion from T4 → T3 by adaptive deiodinase responses — the body preferentially converts the remaining T4 to the more active T3 to compensate ^[1]
When IS fT3 useful?	In hyperthyroidism — to detect T3 toxicosis (where only fT3 is elevated, fT4 is normal) ^[1]

Summary: Which Thyroid Hormones to Measure When

Suspected Condition	Measure	Reasoning
Hypothyroidism	TSH + fT4	fT3 not needed — can be normal in hypothyroidism due to adaptive deiodination
Hyperthyroidism	TSH + fT4 + fT3	fT3 needed because 2–5% of patients have T3 toxicosis (only fT3 elevated)
Monitoring T4 replacement	TSH (after 6–8 weeks equilibration)	Once TSH has normalised, it becomes a reliable monitor

These determine the aetiology (autoimmune vs non-autoimmune) and guide management decisions, particularly in subclinical hypothyroidism.

Antibody	Target	Significance in Hypothyroidism
Anti-thyroid peroxidase (TPO) antibodies	TPO enzyme on apical surface of follicular cells	The most important antibody in hypothyroidism. Positive in 90–100% of Hashimoto's thyroiditis ^[1]. Present in 10–15% of the normal population (subclinical autoimmunity). Predicts progression from subclinical → overt hypothyroidism (~4.3% per year if TPOAb+)
Anti-thyroglobulin (TG) antibodies	Thyroglobulin protein in colloid	Positive in 80–90% of Hashimoto's thyroiditis ^[1]. Less specific than TPOAb. Important in thyroid cancer follow-up (interferes with thyroglobulin measurement) ^[10]
Thyrotropin receptor antibodies (TRAb)	TSH receptor on follicular cells	Primarily relevant in Graves' disease (80–90% positive) ^[1]. In hypothyroidism, TSH receptor-blocking antibodies (a subtype of TRAb) can cause atrophic thyroiditis — they block TSH action instead of stimulating it. Also relevant in neonatal hypothyroidism (maternal blocking antibodies crossing placenta)

Antibody prevalence table ^[1]:

Condition	Anti-TSH	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: A positive anti-TPO in a patient with subclinical hypothyroidism means they are more likely to progress to overt disease AND more likely to benefit from early T4 treatment ^[1].

These are not diagnostic of hypothyroidism per se but are essential for identifying complications and preparing for treatment.

Investigation	Why	Expected Findings in Hypothyroidism
CBC with differentials	Baseline to prepare patient for thionamides which can cause agranulocytosis (more relevant in hyperthyroidism treatment, but done as part of complete workup) ^[1]. Also detects anaemia (common in hypothyroidism)	Normocytic or macrocytic anaemia (ACD, B12/folate deficiency). May see low WCC if concurrent autoimmune neutropenia
LFT	Baseline LFT to prepare patient for thionamides which can cause hepatotoxicity ^[1]. Hypothyroidism itself can cause mild transaminase elevation	Mildly elevated AST/ALT (due to myopathy → CK leak can also cause AST elevation). Elevated CK (skeletal muscle origin)
Lipid panel	Hypothyroidism causes secondary hypercholesterolaemia (↓ LDL receptors)	↑ Total cholesterol, ↑ LDL-cholesterol, ↑ triglycerides. Correct with T4 treatment before starting a statin
Serum electrolytes (Na⁺, K⁺)	Hypothyroidism causes hyponatraemia (↓ free water clearance, ↑ ADH)	Hyponatraemia — always check TFTs in unexplained hyponatraemia
Serum calcium and phosphate	Relevant if post-thyroidectomy (assess for hypoparathyroidism) or if concurrent autoimmune hypoparathyroidism	Hypocalcaemia if parathyroid glands damaged/removed ^[10]
Serum CK (creatine kinase)	Hypothyroid myopathy causes CK elevation — can be mistaken for MI or rhabdomyolysis	Elevated CK (skeletal muscle isoform, not cardiac)
Serum glucose	Hypothyroidism can cause hypoglycaemia (↓ gluconeogenesis, ↓ glycogenolysis), especially in myxoedema coma	Low-normal or ↓ glucose
Prolactin	If galactorrhoea or menstrual disturbance present. ↑ TRH → ↑ prolactin	Mildly elevated prolactin (usually < 100 ng/mL — if > 200, think prolactinoma)

4. Imaging Studies

Thyroid USG is routine for all patients with goitre or palpable nodule ^[3]^[11].

Aspect	Detail
Modality	B-mode real-time ultrasonography ^[3]
Advantages	Non-invasive, no radiation, convenient, and cheap ^[3]
Sensitivity/Specificity	Highly sensitive but relatively low specificity ^[3]
Roles ^[3]^[11]	Extend physical examination
	Select nodules for FNAC
	Guide needle aspiration
	Assess size of goitre ^[11]
	Assess nodule number and suspicious features ^[11]
	Assess cervical lymph nodes (esp. deep nodes, e.g. level VI nodes) ^[11]
	Assess retrosternal extension ^[11]
NOT recommended as	A screening test in the general population ^[3]

Findings specific to hypothyroidism:

Hashimoto's thyroiditis: Diffusely hypoechoic gland (due to lymphocytic infiltration replacing normal follicular tissue), heterogeneous echotexture, may show pseudo-nodular pattern, often with increased vascularity on Doppler. The gland may be enlarged (early) or atrophic (late)
Atrophic thyroiditis: Small, hypoechoic gland
Post-thyroidectomy: Absent gland (total) or small remnant (subtotal)

Concurrent nodule assessment — because even in a hypothyroid patient, you must evaluate for coexisting thyroid nodules:

Sonographic features suspicious of malignancy: "SHIT CME" ^[11] — most important are solid and hypoechoic:

S — Solid nodule
H — Hypoechoic nodule
I — Irregular margin
T — Taller than wide (AP > TS)
C — Chaotic central vascularity
M — Microcalcifications
E — Extrathyroidal extension

USG risk stratification and FNAC criteria ^[1]^[3]^[11]:

Sonographic Pattern	Ultrasound Features	Risk of Malignancy	FNA Size Cutoff
High suspicion	Solid hypoechoic nodule + ≥ 1 suspicious feature (microcalcifications, taller than wide, irregular margins, ETE)	> 70–90%	FNA if ≥ 1 cm
Intermediate suspicion	Hypoechoic solid nodule with smooth margins WITHOUT other suspicious features	10–20%	FNA if ≥ 1 cm
Low suspicion	Isoechoic or hyperechoic nodule with no suspicious features	5–10%	FNA if ≥ 1.5 cm
Very low suspicion	Partially cystic nodule	≤ 3%	FNA if ≥ 2 cm or observe
Benign	Purely cystic nodules	≤ 1%	No biopsy

While FNAC is primarily used for thyroid nodule assessment rather than diagnosing hypothyroidism itself, it is critical when a patient with hypothyroidism has coexisting nodules — remember, Hashimoto's is a risk factor for thyroid lymphoma.

FNAC is diagnostic and therapeutic for thyroid cysts ^[11].

Core needle biopsy is NOT performed because the thyroid is a very vascularised structure and core biopsy would lead to massive bleeding. FNAC is very accurate in identifying type of thyroid cancer ^[10].

Bethesda Classification ^[1]^[3]:

Class	Diagnostic Category	Cancer Risk	Usual Management
I	Non-diagnostic	1–4%	Repeat FNA
II	Benign	0–3%	Clinical follow-up
III	AUS or FLUS	5–15%	Repeat FNA
IV	Follicular neoplasm	15–30%	Surgical lobectomy
V	Suspicious of malignancy	60–75%	Surgical lobectomy (FS) + TT
VI	Malignant	97–99%	Total thyroidectomy (TT)

AUS = atypia of undetermined significance; FLUS = follicular lesion of undetermined significance ^[3]

Limitation: Limited assessment of architecture — cannot distinguish follicular adenoma vs carcinoma ^[11]. This is because follicular carcinoma is defined by capsular or vascular invasion, which requires histological (not cytological) assessment.

Aspect	Detail
Isotopes used	I-123, Tc-99m, or I-131 ^[3]
Role in hypothyroidism	Limited. NOT recommended for routine diagnostic use ^[1]
Primary indication	Only in patients with ↓ TSH (clinical or subclinical hyperthyroidism) + nodules — to determine functional status of nodule ^[1]^[11]
Why NOT in hypothyroidism?	NOT performed in euthyroid or ↑ TSH states since the thyroid nodule will never be hyperfunctioning and will require USG ± FNAC to confirm anyways ^[1]
Interpretation	Hot nodules (uptake > surrounding tissue) → almost never malignant → do NOT require FNAC ^[1]
	Cold nodules (uptake < surrounding tissue) → 10–20% risk of cancer → require FNAC if sonographic criteria met ^[1]
Use in hypothyroidism diagnosis	In Hashimoto's: diffusely reduced, patchy uptake (destroyed follicles can't trap iodine). However, this is NOT how we diagnose Hashimoto's (antibodies + clinical context suffice)
Role in specific scenarios	Differentiate between toxic nodule (→ hemithyroidectomy) vs toxic MNG / Graves' (→ total thyroidectomy) ^[11] — relevant to thyrotoxicosis, not hypothyroidism

Diagnosis of malignancy: low sensitivity and specificity on scintigraphy ^[3] — this is why we rely on USG + FNAC, not scans.

Investigation	Indication	Key Points
CT scan of neck	Only when: (1) Retrosternal goitre, (2) Locally advanced thyroid cancer ^[11]	Retrosternal goitre requires CT because: (1) Cannot be visualised by USG, (2) Surgical planning, (3) Retrosternal goitre may be malignant ^[11]. CAUTION: Use non-iodinated contrast if RAI therapy is planned (iodinated contrast interferes with RAI uptake for 6–8 weeks)
MRI pituitary	Suspected central hypothyroidism	Assess for pituitary tumour, empty sella, infiltrative disease. Remember: longstanding primary hypothyroidism → thyrotroph hyperplasia → can mimic pituitary tumour ^[5]
CXR (thoracic inlet view)	Assess for retrosternal extension, tracheal deviation, tracheal compression ^[3]	May show mediastinal widening from retrosternal goitre
PET scan	NO diagnostic role in thyroid diseases ^[11] — even malignant nodules can have low uptake	Exception: PET-avid thyroid incidentalomas discovered during PET for other cancers have a ~30–35% risk of malignancy → warrant FNAC

Investigation Hierarchy — What's Routine vs Selective

Adapted from the surgical approach ^[11]:

Routine for ALL patients	Selective (specific indications only)
History + Physical examination	Thyroid scan — only if ↓ TSH + nodules
Thyroid function test (TFT)	CT scan — only for retrosternal goitre or locally advanced cancer
USG thyroid ± FNAC	PET scan — NO diagnostic role at all

For hypothyroidism specifically, add: anti-TPO antibodies, CBC, lipid panel, electrolytes.

5. Special Investigations

Universal neonatal screening for congenital hypothyroidism is performed in Hong Kong (and most developed countries)
Heel prick blood spot test at 24–72 hours of life
Measures TSH (primary screening strategy in most programmes) — elevated TSH triggers reflex fT4 measurement
Why? Thyroid hormones are critical for CNS myelination in the first 2–3 years — undetected congenital hypothyroidism causes irreversible cretinism ^[1]

When you suspect central (secondary/tertiary) hypothyroidism:

Investigation	Purpose	Key Finding
Full anterior pituitary hormone panel	Assess for panhypopituitarism	Check: cortisol (8 am), LH/FSH, oestradiol/testosterone, IGF-1, prolactin. CORTISOL FIRST — must exclude adrenal insufficiency before starting T4
MRI pituitary with gadolinium	Visualise sellar/suprasellar pathology	Pituitary adenoma, empty sella, infiltrative disease. Beware: thyrotroph hyperplasia from primary hypothyroidism can mimic adenoma ^[5]
Formal visual field testing	Assess for optic chiasm compression	Bitemporal hemianopia in pituitary macroadenoma
Dynamic pituitary testing (TRH stimulation test)	Distinguish secondary (pituitary) from tertiary (hypothalamic)	Rarely used in modern practice — MRI has largely replaced it. In pituitary disease: TSH does not rise after TRH injection. In hypothalamic disease: delayed but exaggerated TSH rise

CRITICAL SAFETY POINT

In central hypothyroidism, ALWAYS check serum cortisol and exclude coexisting adrenal insufficiency BEFORE starting levothyroxine. Why?

Levothyroxine increases the body's metabolic rate → increases cortisol metabolism → if the patient already has ACTH deficiency (common in panhypopituitarism), starting T4 will deplete their already low cortisol → acute adrenal crisis (hypotension, shock, death).

The rule: Cortisol FIRST, then Thyroxine.

For a patient with confirmed or suspected hypothyroidism, here is the systematic investigation approach:

Category	Investigation	Purpose
Confirm diagnosis	TSH	Screen — elevated in primary, low/normal in central
	fT4	Confirm and grade severity (subclinical vs overt)
Determine aetiology	Anti-TPO antibodies	Autoimmune (Hashimoto's 90–100%, atrophic thyroiditis)
	Anti-Tg antibodies	Supportive of autoimmune aetiology; interference with Tg tumour marker
	Clinical history	Post-thyroidectomy, post-RAI, drugs (amiodarone, lithium, checkpoint inhibitors), neck irradiation
Assess complications	CBC	Anaemia (ACD, iron deficiency from menorrhagia, B12/folate deficiency)
	Lipid panel	Hypercholesterolaemia (↓ LDL receptors)
	Electrolytes	Hyponatraemia (↑ ADH, ↓ free water clearance)
	CK	Elevated in hypothyroid myopathy
	LFT	Mild transaminase elevation
	Serum calcium	If post-thyroidectomy → hypoparathyroidism
Image the gland	Thyroid USG	Assess gland morphology, identify coexisting nodules, guide FNAC
If nodule found	FNAC (USG-guided)	Bethesda classification; exclude malignancy
	Thyroid scintigraphy	Only if TSH is LOW (to assess hot vs cold nodule)
If central hypothyroidism suspected	MRI pituitary	Sellar pathology
	Full pituitary panel	Cortisol FIRST, then LH/FSH, IGF-1, prolactin
	Visual fields	Chiasmal compression

Finding	Interpretation
↑ TSH + ↓ fT4	Primary overt hypothyroidism
↑ TSH + normal fT4	Subclinical hypothyroidism
Normal/low TSH + ↓ fT4	Central hypothyroidism OR sick euthyroid syndrome
Anti-TPO strongly positive	Hashimoto's thyroiditis (or atrophic thyroiditis)
Diffusely hypoechoic, heterogeneous thyroid on USG	Hashimoto's thyroiditis
Small/absent thyroid on USG	Atrophic thyroiditis, post-thyroidectomy, congenital dysgenesis
Cold nodule on scintigraphy	10–20% risk of malignancy → needs FNAC
Hot nodule on scintigraphy	Almost never malignant → treat as toxic adenoma, no FNAC needed
Elevated CK	Hypothyroid myopathy (skeletal, not cardiac)
↑ Cholesterol, ↑ LDL	Secondary dyslipidaemia from hypothyroidism
Hyponatraemia	↑ ADH + ↓ free water clearance
Macrocytic anaemia + anti-parietal cell Ab	Concurrent pernicious anaemia (autoimmune polyglandular)
Pituitary enlargement on MRI + ↑↑ TSH	Thyrotroph hyperplasia (NOT a tumour) — resolves with T4 replacement

High Yield Summary

Diagnosis of hypothyroidism is BIOCHEMICAL — TSH is the first-line test.

TSH interpretation:

↑ TSH = primary (95% of cases). Measure fT4 to distinguish overt (↓ fT4) from subclinical (normal fT4).
Normal/↓ TSH + ↓ fT4 = central hypothyroidism. Needs MRI pituitary + pituitary hormone panel. Check cortisol BEFORE starting T4.

fT3 is NOT needed in hypothyroidism workup — it can be normal in 25% of cases due to adaptive deiodination.

Always measure fT4, never total T4 — total T4 is affected by TBG changes (pregnancy ↑, OCP ↑, nephrotic syndrome ↓).

Anti-TPO antibodies are the key aetiological test — positive in 90–100% of Hashimoto's. Predicts progression of subclinical → overt hypothyroidism.

Thyroid USG is routine for all goitres/palpable nodules. Suspicious sonographic features = SHIT CME. FNA criteria based on ATA risk stratification by sonographic pattern.

Thyroid scintigraphy is NOT for hypothyroidism — only indicated when TSH is LOW + nodules present. Hot = benign (no FNAC), Cold = potentially malignant (needs FNAC).

PET scan has NO diagnostic role in thyroid diseases.

Bethesda classification guides FNAC management: Class I → repeat, Class II → follow-up, Class III → repeat, Class IV → lobectomy, Class V → lobectomy + FS + TT, Class VI → TT.

Baseline bloods: CBC (anaemia), lipids (↑ cholesterol), electrolytes (hyponatraemia), CK (myopathy), calcium (post-thyroidectomy hypoparathyroidism).

Active Recall - Diagnosis and Investigation of Hypothyroidism

References

^[1] Senior notes: felixlai.md (Hypothyroidism: Diagnosis, Biochemical Tests, TFT Interpretation, Thyroid Antibodies, Radionuclide Scan) ^[3] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (USG, FNAC Bethesda, Scintigraphy, Investigation hierarchy) ^[5] Senior notes: felixlai.md (Pituitary adenomas, Thyrotroph hyperplasia, Differential diagnosis of sellar mass) ^[10] Senior notes: felixlai.md (Thyroid cancer diagnosis: biochemical tests, radiological tests, FNAC) ^[11] Senior notes: maxim.md (Approach to thyroid nodules: Investigations, USG features, FNAC, Thyroid scan, CT indications)

Management of Hypothyroidism

The management of hypothyroidism is conceptually straightforward: replace what's missing. The thyroid gland isn't making enough T4 and T3, so we give exogenous thyroid hormone. But the nuances — who to treat, how much to give, how fast to start, and what to watch out for — are where clinical wisdom lies.

Key management decisions depend on:

Severity: Overt vs subclinical vs myxoedema coma
Aetiology: Permanent (Hashimoto's, post-thyroidectomy) vs transient (post-partum thyroiditis, subacute thyroiditis)
Patient factors: Age, cardiovascular disease, pregnancy, coexisting adrenal insufficiency
Context: Primary vs central hypothyroidism (the latter demands cortisol replacement first)

C. Treatment Modalities

1. Levothyroxine (T4) — The Mainstay

"Levothyroxine" — let's break it down: "levo" = left-handed (the L-isomer, which is the biologically active form), "thyroxine" = T4. This is synthetic T4, identical to what the thyroid gland produces.

Aspect	Detail
Drug	Levothyroxine (T4)
Indication	Routine replacement therapy — for hypothyroidism of any cause ^[1]
Why T4 and not T3?	Due to its longer half-life (t½) — T4 has a half-life of ~7 days vs T3's ~1 day. This means take once daily only with stable serum levels throughout the day ^[1]. T4 is also a "pro-hormone" that is peripherally converted to the more active T3 by deiodinases, providing a steady, physiological supply of T3 to all tissues
Starting dose	Young, otherwise healthy adults: 1.6 mcg/kg/day (typically 50–100 mcg/day)
	Elderly or patients with IHD: Start LOW — 12.5–25 mcg/day and increase by 12.5–25 mcg every 6–8 weeks. Why? Because suddenly increasing the metabolic rate in a patient with coronary artery disease increases myocardial oxygen demand → can precipitate angina, arrhythmias, or MI
Administration	Take on an empty stomach, 30–60 minutes before breakfast (or at bedtime, 3+ hours after last meal). Why? Because food, calcium, iron, and PPI reduce absorption
Target	Normalise TSH to within the reference range (0.4–4.0 mU/L; often aim for 0.5–2.5 mU/L in most patients)
Monitoring	Check TSH 6–8 weeks after starting or dose adjustment (it takes this long for the HPT axis to re-equilibrate). Once stable, check TSH every 6–12 months

These are really the consequences of over-replacement (iatrogenic thyrotoxicosis) or under-recognised contraindications:

Adverse Effect	Mechanism	Detail
Acute adrenal crisis	↑ Metabolic clearance of adrenocortical hormones → ↓ cortisol and aldosterone	Contraindicated in patient with adrenal insufficiency — T4 increases the metabolic rate including cortisol metabolism. If the patient already has low cortisol (e.g. panhypopituitarism, Addison's), starting T4 depletes it further → Addisonian crisis (hypotension, shock, death) ^[1]
Deterioration of CVS disease by thyrotoxicosis	↑ Workload of heart and worsens ischaemic symptoms	Angina / Arrhythmias / Cardiac failure — over-replacement or too-rapid dose escalation in elderly/IHD patients increases myocardial O₂ demand, β-receptor sensitivity, and chronotropy ^[1]
Over-suppression of TSH (chronic over-replacement)	Sustained supraphysiological T4 levels	Atrial fibrillation (3× risk if TSH < 0.1 mU/L), osteoporosis (especially post-menopausal women — T4 excess increases bone turnover and resorption)
Under-replacement	Insufficient dose	Persistent symptoms of hypothyroidism, elevated TSH

The Two Absolute Contraindications to Starting T4 Without Prior Action

Untreated adrenal insufficiency — give hydrocortisone FIRST, then T4. (Applies to both central hypothyroidism with panhypopituitarism AND primary hypothyroidism + concurrent Addison's disease)
Acute MI / unstable angina — stabilise the cardiac condition first, then start T4 at very low doses with close cardiac monitoring

These two situations are exam favourites. The logic is the same: don't increase metabolic demand in a body that can't handle it.

Drug/Substance	Effect	Mechanism
Calcium carbonate, iron supplements	↓ T4 absorption	Chelation in the GI tract — separate by ≥ 4 hours
PPIs, antacids, sucralfate	↓ T4 absorption	↑ gastric pH reduces dissolution of T4 tablet
Cholestyramine, colestipol	↓ T4 absorption	Bile acid sequestrants bind T4 in the gut
Carbamazepine, phenytoin, rifampicin	↑ T4 metabolism	CYP450 enzyme induction → increased T4 clearance → may need higher T4 doses
Oestrogen (OCP, HRT)	↑ TBG → ↑ total T4 but fT4 may drop slightly	May need dose adjustment (increase by ~25%)
Pregnancy	↑ TBG, ↑ blood volume, ↑ placental deiodination	T4 dose typically needs to increase by 30–50% as early as week 4–6. Monitor TSH every 4 weeks in first trimester

"Liothyronine" — "lio" = smooth (variant prefix), "thyronine" = T3. This is synthetic T3.

Aspect	Detail
Drug	Liothyronine (T3)
Indication	Acute severe hypothyroid state — hypothyroid coma (hypoglycaemia) — due to its faster onset ^[1]
Onset	Hours (vs T4 which takes days to weeks for full effect)
Half-life	~1 day (vs T4's ~7 days)
Why not for routine use?	Short half-life means fluctuating serum levels → difficult to maintain steady state → peaks and troughs cause alternating thyrotoxic and hypothyroid symptoms. T4 is more physiological for chronic replacement
Adverse effects	Thyrotoxicosis — overdose leading to hyperthyroidism ^[1]
Special use	In preparation for RAI ablation in thyroid cancer patients who cannot tolerate prolonged hypothyroidism — start T3 therapy which has a shorter t½ and stop for 2 weeks prior to RAI ablation (vs stopping T4 for 4 weeks) ^[10]

3. Management by Clinical Scenario

This is the most common scenario — patient has ↑ TSH + ↓ fT4.

Management:

Levothyroxine (T4) — routine replacement therapy for hypothyroidism of any cause ^[1]
Starting dose: 1.6 mcg/kg/day in young, healthy patients (typically 50–100 mcg/day)
Elderly / IHD patients: start 12.5–25 mcg/day, increase by 12.5–25 mcg every 6–8 weeks
Monitor: TSH every 6–8 weeks until stable, then every 6–12 months
Goal: TSH within normal range (0.4–4.0 mU/L)
Treatment is usually lifelong for permanent causes (Hashimoto's, post-thyroidectomy, post-RAI)
For transient causes (subacute thyroiditis, post-partum thyroiditis): trial of T4, then attempt dose reduction after 6–12 months to reassess if hypothyroidism has resolved

This is the most controversial area — who benefits from treatment?

Decision framework ^[1]:

TSH Level	Anti-TPO Status	Symptoms?	Action
> 10 mU/L	Any	Any	Treat — high risk of progression to overt hypothyroidism (annual rate ~5%). Associated with cardiovascular risk
4.5–10 mU/L	TPOAb+	Any	T4 treatment — TPOAb positivity predicts progression (~4.3% per year) ^[1]
4.5–10 mU/L	TPOAb–	Symptomatic	T4 treatment — therapeutic trial. Reassess symptoms at 3–6 months. If no improvement, may discontinue ^[1]
4.5–10 mU/L	TPOAb–	Asymptomatic	Annual follow-up — repeat TSH yearly. Treat if TSH rises or symptoms develop ^[1]

Special populations:

Pregnancy: treat ALL subclinical hypothyroidism (TSH > trimester-specific upper limit). Untreated subclinical hypothyroidism in pregnancy is associated with adverse obstetric and neurodevelopmental outcomes
Elderly ( > 70 years): be cautious — mildly elevated TSH may be physiological with ageing. Overtreating may cause AF and osteoporosis. Generally avoid treating if TSH < 10 and asymptomatic in the very elderly

Critical management sequence:

Check cortisol and exclude adrenal insufficiency FIRST ^[1]
If adrenal insufficiency present → start hydrocortisone FIRST (typically 15–25 mg/day in divided doses) → stabilise for several days
Then start levothyroxine
Cannot use TSH to monitor — TSH is already low/inappropriate. Monitor fT4 levels instead (aim for upper half of the normal range)
Treat the underlying cause — pituitary tumour (surgery, radiation), infiltrative disease, etc.

This is an extremely common scenario in Hong Kong (high surgical volume for thyroid cancer and MNG).

After hemithyroidectomy ^[10]:

Do NOT start T4 therapy immediately postoperatively
Measure serum TSH 6 weeks after surgery and determine the need for T4 based upon TSH and evaluation of postoperative disease status ^[10]
About 10–20% will develop hypothyroidism after hemithyroidectomy ^[3]

After total thyroidectomy ^[10]:

100% will need T4 replacement — the entire gland has been removed ^[2]
Depends on the need for RAI ablation ^[10]:

Situation	Action
Patient does NOT need RAI ablation	Start T4 therapy immediately postoperatively ^[10]
Patient requires RAI ablation and CAN tolerate prolonged hypothyroidism	Withhold T4 therapy. Stop T4 4 weeks prior to RAI ablation — this allows TSH to rise, which promotes RAI uptake by residual thyroid tissue/tumour ^[10]
Patient requires RAI ablation and CANNOT tolerate prolonged hypothyroidism (e.g. CVS disease)	Start T3 therapy (shorter t½) and stop for 2 weeks prior to RAI ablation ^[10]. Alternatively, use recombinant human TSH injection (rhTSH/Thyrogen®) — this stimulates RAI uptake without the patient needing to become hypothyroid ^[10]

Why Withdraw Thyroid Hormones Before RAI?

The principle is elegant: after total thyroidectomy, any remaining thyroid tissue (normal remnant or cancer cells) still has TSH receptors and sodium-iodide symporters (NIS). By withdrawing T4/T3:

TSH rises dramatically (no negative feedback)
TSH stimulates NIS expression on residual cells
NIS traps the radioactive iodine (I-131) into the cells
I-131 emits beta radiation locally → destroys those cells

If you keep the patient on T4 (suppressing TSH), the residual cells won't upregulate NIS → won't take up the RAI → the ablation fails.

The alternative is recombinant human TSH — you inject exogenous TSH to stimulate uptake without needing the patient to be hypothyroid. This is especially useful in patients with CVS disease who cannot tolerate prolonged hypothyroidism ^[10].

For thyroid cancer patients, levothyroxine serves a dual purpose ^[12]^[13]:

Replacement — prevent hypothyroidism
Suppression — high TSH stimulates tumour growth (because differentiated thyroid cancer cells retain TSH receptors). By giving supraphysiological T4, you suppress TSH below normal → less stimulation of any residual cancer cells

Target TSH depends on risk stratification ^[12]:

Risk Category	Features	TSH Target
Low risk	None of the following features	No TSH suppression (0.5–2.0 mIU/L)
Intermediate risk	T3, N1, aggressive histology, vascular invasion +ve	Low TSH suppression (0.1–0.5 mIU/L)
High risk	T4, M1, incomplete resection	High TSH suppression ( < 0.1 mIU/L)

Note that the low risk group does NOT require TSH suppression ^[12] — this is a recent change in guidelines. Over-suppression causes AF and osteoporosis, so we only suppress when the benefit (reduced recurrence risk) outweighs the harm.

Precautions of T4 suppression therapy ^[10]:

Osteoporosis → Calcium supplements required
Atrial fibrillation and cardiac dysfunction → May withhold treatment in elderly or those with pre-existing cardiac disease ^[10]

This is the most severe, life-threatening form of hypothyroidism. It is a medical emergency with mortality of 20–60%.

General features ^[1]:

Severe hypothyroidism with hypothermia, respiratory failure with hypoxia, and coma

Precipitants (important — often exam-tested):

Infection (most common), cold exposure, trauma, surgery
Sedatives/opioids, non-compliance with T4
Stroke, GI bleeding, heart failure

General management ^[1]:

Treatment of precipitating causes — identify and treat infection, stop offending drugs
Maintenance of body temperature — passive rewarming (blankets). Avoid active external rewarming (causes peripheral vasodilation → further hypotension)
Correction of hypoglycaemia with D10 — hypothyroidism decreases gluconeogenesis and glycogenolysis ^[1]
Correction of fluid and electrolytes with NS ± vasopressors — patients are typically hyponatraemic (dilutional from ↑ ADH + ↓ free water clearance) and hypotensive ^[1]
Mechanical ventilation — hypoventilation and CO₂ retention are common (↓ respiratory drive + respiratory muscle weakness + possible pleural effusions)

Medical treatment ^[1]:

Liothyronine (T3) — faster onset for the acute situation
Levothyroxine (T4) — IV loading dose (200–500 mcg IV bolus, then 50–100 mcg/day IV). The large initial dose is needed because the distribution volume is large and the patient may have near-zero circulating T4
Hydrocortisone — empirical IV hydrocortisone (50–100 mg IV q8h). Why? Because:
1. Coexisting adrenal insufficiency is common (autoimmune polyglandular syndrome, or panhypopituitarism)
2. Even without adrenal insufficiency, the stress of myxoedema coma increases cortisol demand
3. Starting T4/T3 increases cortisol metabolism → can precipitate adrenal crisis
4. Always give hydrocortisone before or simultaneously with T4/T3 — never after

Myxoedema Coma Treatment Triad

Remember the three-drug regimen:

T4 (IV levothyroxine) ± T3 (IV liothyronine) — replace thyroid hormones
IV Hydrocortisone — prevent adrenal crisis
Supportive care — warm, glucose, fluids, ventilate, treat precipitant

The order matters: Hydrocortisone → then T4/T3 (or simultaneously). Never give thyroid hormones alone without cortisol coverage in this setting.

Aetiology	Management Approach
Hashimoto's thyroiditis	Lifelong levothyroxine. Monitor TSH. Goitre usually shrinks with T4 (reduced TSH drive). If goitre causes compression → thyroidectomy (4C indications: CA, Compression, Cosmetic, Patient Concern) ^[2]^[12]
Post-thyroidectomy	See Scenario 4 above. Total thyroidectomy → lifelong T4. Hemithyroidectomy → check TSH at 6 weeks ^[10]
Post-RAI (for Graves' disease)	Expected outcome. Start lifelong T4 when hypothyroidism develops (may be delayed weeks to months)
Drug-induced (amiodarone, lithium)	If the offending drug can be stopped → hypothyroidism may resolve. If the drug must continue (e.g. amiodarone for life-threatening arrhythmia) → add levothyroxine while continuing the drug
Transient (subacute thyroiditis, post-partum)	Short-term T4 replacement during the hypothyroid phase. Attempt dose reduction after 6–12 months. Many recover spontaneously. Post-partum thyroiditis: ~20–30% develop permanent hypothyroidism
Congenital hypothyroidism	Immediate levothyroxine initiation (within 2 weeks of diagnosis). Dose: 10–15 mcg/kg/day in neonates (proportionally higher than adults because of rapid CNS growth). Goal: normalise TSH and fT4 rapidly. Lifelong treatment. Follow-up includes neurodevelopmental assessment
Iodine deficiency	Iodine supplementation. May need T4 if gland is significantly damaged. Public health approach: iodised salt programmes
Central hypothyroidism	Treat underlying cause (pituitary surgery if tumour). Cortisol replacement before T4. Monitor fT4 (not TSH)

Surgery is NOT a treatment for hypothyroidism per se — but it may be needed for the underlying cause or associated goitre.

Indications for thyroidectomy (4C) ^[12]:

CA thyroid — cancer (most important)
Compression — pressure symptoms (dysphagia, stridor, dyspnoea)
Cosmetic concern — large goitre
Uncontrolled thyrotoxicosis — not applicable to hypothyroidism, but relevant when a hypothyroid patient also has nodules

Types of thyroidectomy ^[3]^[12]:

Procedure	Definition	Indication	Post-op Hypothyroidism Risk
Hemithyroidectomy	Resection of one lobe + isthmus	Uninodular goitre, low-risk small thyroid cancer	10–20% ^[3]
Total thyroidectomy	Resection of both lobes + isthmus + pyramidal lobe	Symptomatic MNG, high-risk thyroid cancer, Graves' disease	100% — lifelong T4 required ^[3]
Subtotal thyroidectomy	Resection of > 1/2 of both lobes + isthmus	Rarely indicated ^[3]

Thyroidectomy complications relevant to hypothyroidism ^[2]:

Hypothyroidism (late complication) — expected after total thyroidectomy. Manage with lifelong T4
Parathyroid injury — only in total thyroidectomy. Most common complication, but usually transient ^[2]
- S/S: perioral numbness, carpopedal spasm, Chvostek's sign, Trousseau's sign ^[2]
- Severe hypocalcaemia can lead to laryngospasm requiring emergency intubation / surgical airway ^[2]
- Mx: Ca + vit D supplement (acute: IV Ca gluconate) ^[2]
RLN injury — unilateral → hoarseness; bilateral → airway obstruction ^[2]
EBSLN injury — loss of high pitch, poor volume, easy fatigue ^[2]

Pre-operative evaluation for thyroidectomy ^[12]:

Maintain biochemically euthyroid (critical for thyrotoxic patients; hypothyroid patients should be euthyroid on T4 before elective surgery)
Vocal cord function by laryngoscopy — baseline documentation
Monitor Ca and vit D level and supplement accordingly (post-op hypoPTH / hungry bone syndrome) ^[12]

Parameter	Frequency	Target	Notes
TSH	Every 6–8 weeks after dose change; every 6–12 months once stable	0.4–4.0 mU/L (general population)	In pregnancy: trimester-specific targets. In thyroid cancer: risk-stratified suppression targets
fT4	Only in central hypothyroidism (TSH unreliable)	Upper half of normal range	Also useful early in treatment before TSH equilibrates
Symptoms	Every visit	Resolution of hypothyroid symptoms	If symptoms persist despite normal TSH, consider: compliance, absorption issues, T4/T3 combination therapy (controversial)
Lipid panel	Recheck 3–6 months after achieving euthyroidism	Improvement in cholesterol	Persistent dyslipidaemia after euthyroidism achieved → treat as primary dyslipidaemia
Bone density (DEXA)	Post-menopausal women on suppressive T4 therapy	Monitor for osteoporosis	TSH suppression accelerates bone loss
Cardiac monitoring (ECG)	Elderly / IHD patients during dose titration	No new ischaemia or arrhythmia

Common Causes of Persistent Hypothyroid Symptoms Despite 'Normal' TSH

Non-compliance — most common! T4 must be taken daily on an empty stomach
Absorption issues — concurrent calcium, iron, PPI, coeliac disease, post-bariatric surgery
Inadequate dose — weight gain, pregnancy, drug interactions (OCP, carbamazepine, rifampicin)
Wrong diagnosis — symptoms attributed to hypothyroidism were actually from another condition (depression, sleep apnoea, anaemia)
T3 conversion issue — rare; some patients may benefit from combination T4+T3 therapy (controversial, not standard practice)

G. Special Situations

T4 dose typically needs to increase by 30–50% as early as 4–6 weeks gestation
Why? ↑ TBG (oestrogen-driven) → ↑ total T4 bound → ↓ fT4 → ↑ TSH. Also: ↑ blood volume, ↑ placental type 3 deiodinase (inactivates T4)
Monitor TSH every 4 weeks in the first trimester, then every 4–6 weeks
Target TSH: trimester-specific (generally < 2.5 mU/L in the first trimester, < 3.0 in the second and third — though 2017 ATA guidelines suggest population-based references)
After delivery: reduce dose back to pre-pregnancy level and recheck TSH at 6 weeks post-partum

As discussed: always replace cortisol BEFORE thyroxine
This applies to: panhypopituitarism (most common), autoimmune polyglandular syndrome type 2 (Hashimoto's + Addison's + T1DM), isolated ACTH deficiency
The rationale: T4 increases metabolic clearance of adrenocortical hormones → ↓ cortisol and aldosterone → acute adrenal crisis ^[1]

High Yield Summary

Treatment of choice: Levothyroxine (T4) — for ALL causes of hypothyroidism. Once daily, long half-life, physiological conversion to T3 peripherally.

Liothyronine (T3): Only for acute severe hypothyroidism (myxoedema coma) due to faster onset. Also used as bridge therapy before RAI ablation (stop 2 weeks before, vs T4 stopped 4 weeks before).

Overt hypothyroidism: Start T4. Young/healthy: 1.6 mcg/kg/day. Elderly/IHD: start LOW (12.5–25 mcg) and titrate slowly.

Subclinical hypothyroidism: Treat if TSH > 10, or if TPOAb+ or symptomatic. Otherwise annual follow-up.

Central hypothyroidism: CHECK CORTISOL FIRST. Replace hydrocortisone before T4. Monitor fT4 (not TSH).

Post-thyroidectomy: Hemithyroidectomy → check TSH at 6 weeks, 10–20% need T4. Total thyroidectomy → 100% need lifelong T4. If RAI needed → withhold T4 for 4 weeks (or T3 for 2 weeks, or use rhTSH).

T4 suppression in thyroid cancer: Low risk → TSH 0.5–2.0 (no suppression needed). Intermediate → 0.1–0.5. High risk → < 0.1.

Myxoedema coma: IV T4 loading ± IV T3 + IV hydrocortisone + supportive care (warm, glucose, fluids, ventilate, treat precipitant). Hydrocortisone FIRST or simultaneously.

Two absolute rules before starting T4: (1) Exclude adrenal insufficiency — cortisol first, then T4. (2) In IHD patients — start low, go slow.

Monitoring: TSH every 6–8 weeks until stable, then 6–12 monthly. In central hypothyroidism, monitor fT4 instead.

Drug interactions: Separate T4 from calcium/iron by 4 hours. Increase dose if on OCP, carbamazepine, rifampicin, or pregnant.

Active Recall - Management of Hypothyroidism

References

^[1] Senior notes: felixlai.md (Treatment of hypothyroidism, Management of myxoedema coma, Biochemical tests, TFT interpretation, Diagnostic algorithm) ^[2] Senior notes: maxim.md (Thyroidectomy complications: RLN injury, parathyroid injury, EBSLN injury, post-op dyspnoea DDx) ^[3] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (Benign thyroid nodules surgical treatment, RAI ablation, Management considerations) ^[10] Senior notes: felixlai.md (Thyroid cancer: thyroid hormone replacement post-thyroidectomy, RAI ablation indications and preparation) ^[12] Senior notes: maxim.md (Thyroxine roles and TSH targets, Thyroidectomy indications 4C, Pre-op evaluation, Extent of resection) ^[13] Lecture slides: Management of differentiated thyroid carcinoma.pdf (Treatment strategy, T4 suppressive therapy, RAI ablation, ATA guidelines)

Complications of Hypothyroidism

Complications of hypothyroidism can be divided into two broad categories:

Complications of the disease itself — what happens when hypothyroidism is untreated or undertreated
Complications of the treatment — what happens when levothyroxine is over-replaced, or complications from the underlying cause/surgery that led to hypothyroidism

Let's work through each systematically, always explaining the "why" from first principles.

A. Complications of Untreated/Undertreated Hypothyroidism

The underlying principle is simple: thyroid hormones are the body's metabolic thermostat. Without them, every organ system gradually decelerates, and metabolic waste products (particularly glycosaminoglycans) accumulate. Over time, this deceleration becomes dangerous.

Complication	Pathophysiology	Clinical Significance
Accelerated atherosclerosis and coronary artery disease	↓ T3 → ↓ hepatic LDL receptor expression → ↓ LDL clearance → hypercholesterolaemia ^[1]. Also: ↑ homocysteine, ↑ CRP (inflammatory state), endothelial dysfunction, diastolic hypertension (↑ SVR from ↓ vasodilatory effect of T3). All of these synergistically promote atherogenesis	Hypothyroidism is an independent cardiovascular risk factor. Always check TFTs in patients with premature atherosclerosis or unexplained dyslipidaemia. The dyslipidaemia is reversible with T4 treatment
Diastolic hypertension	T3 normally relaxes vascular smooth muscle (↓ SVR). In hypothyroidism: ↑ SVR → ↑ diastolic BP. Also ↓ cardiac output → baroreceptor-mediated vasoconstriction	~30% of hypothyroid patients have diastolic hypertension. Resolves with T4 replacement
Pericardial effusion	↑ Capillary permeability + ↓ lymphatic drainage + glycosaminoglycan (GAG) deposition in pericardial space → slow fluid accumulation ^[1]	Usually slow-onset and large (can be massive — > 1L) but rarely causes tamponade because the pericardium stretches gradually. Resolves with T4 treatment
Bradycardia and ↓ cardiac output	↓ Chronotropic effect (T3 normally upregulates β1-adrenergic receptors and Na⁺/K⁺-ATPase in cardiomyocytes) + ↓ inotropy ^[1]	Can lead to haemodynamic compromise, especially in elderly. Contributes to peripheral cyanosis and exercise intolerance
Heart failure	Combination of ↓ contractility, ↑ SVR, pericardial effusion, and in severe cases, myxoedematous cardiomyopathy (GAG infiltration of myocardium)	Rare in isolation but contributes to overall cardiovascular morbidity. Hypothyroidism should be excluded in all new-onset heart failure

Why does hypothyroidism cause diastolic (not systolic) hypertension? In hyperthyroidism, T3 causes vasodilation → ↓ SVR → ↓ diastolic BP (widened pulse pressure). In hypothyroidism, the opposite occurs: ↓ vasodilation → ↑ SVR → ↑ diastolic BP. But cardiac output is low, so systolic BP is normal or low. The result: narrowed pulse pressure with elevated diastolic pressure.

Complication	Pathophysiology	Detail
Depression	↓ Serotonin and noradrenaline turnover in the CNS due to reduced metabolic activity. T3 also has a direct role in serotonergic neurotransmission	Hypothyroidism is a well-recognised treatable cause of depression. Always check TFTs in new-onset depression. May not respond to antidepressants until hypothyroidism is corrected
Cognitive impairment / "pseudodementia"	↓ CNS metabolic rate → slowed synaptic transmission, impaired memory consolidation	Reversible with T4 treatment — critical DDx of dementia in elderly patients
Psychosis ("myxoedema madness")	Severe metabolic derangement in the CNS	Rare but dramatic — can present with paranoia, hallucinations, frank psychosis. Always check TFTs in first-episode psychosis
Peripheral neuropathy	GAG deposition causing nerve entrapment (e.g. carpal tunnel syndrome — carpal tunnel is thickened in myxoedema ^[1]) + metabolic neuropathy (↓ axonal transport)	Carpal tunnel syndrome is the most common entrapment neuropathy. May be bilateral. Also: tarsal tunnel syndrome, other compressive neuropathies
Cerebellar ataxia	Mechanism poorly understood; likely metabolic effect on Purkinje cells	Rare; reversible

Anaemia is common and is multifactorial ^[1]:

Type	Mechanism
Anaemia of chronic disease	Cytokine-mediated ↓ erythropoiesis + ↓ erythropoietin production (most common)
Iron deficiency anaemia	From menorrhagia — ↓ thyroid hormones → altered GnRH pulsatility → anovulatory cycles with heavy, prolonged bleeding ^[1]
Folate deficiency	Bacterial overgrowth — ↓ gut motility → intestinal stasis → bacterial overgrowth → consumption of luminal folate ^[1]
Pernicious anaemia (B12 deficiency)	Associated autoimmune gastritis with anti-intrinsic factor and anti-parietal cell antibodies — part of autoimmune polyglandular syndrome. Presents as macrocytic anaemia

Additionally: Acquired von Willebrand disease (type 1) can occur due to ↓ vWF synthesis, leading to a mild bleeding tendency.

Complication	Pathophysiology
Hypercholesterolaemia	↓ LDL receptors → ↓ LDL clearance → ↑ total cholesterol and LDL. Also ↑ triglycerides. Causes xanthelasmata and accelerated atherosclerosis ^[1]
Hyponatraemia	↓ Free water clearance (↑ ADH secretion + ↓ cardiac output → ↓ renal perfusion → ↑ proximal tubular sodium and water reabsorption + impaired diluting capacity). This is dilutional hyponatraemia — an important DDx of SIADH-like picture
Hypoglycaemia	↓ Gluconeogenesis + ↓ glycogenolysis. Usually mild but can be severe in myxoedema coma. Also related to possible concurrent adrenal insufficiency (autoimmune polyglandular syndrome)
Elevated CK	Hypothyroid myopathy → CK leaks from damaged skeletal muscle. Can be massively elevated (> 10× normal). Important: this is skeletal CK (CK-MM), NOT cardiac CK (CK-MB) — don't mistake it for MI. Also causes elevated AST (which overlaps with both liver and muscle)

Complication	Pathophysiology
Proximal myopathy	↓ Oxidative metabolism in skeletal muscle → weakness. Also GAG deposition in muscle fibres. Tests: ask patient to raise arms above head or stand from squatting ^[1]
Myalgia and stiffness	GAG accumulation + ↓ ATP-dependent relaxation → muscle stiffness
Hoffman syndrome	Rare: hypothyroid myopathy with muscle pseudohypertrophy (muscles look enlarged due to GAG infiltration but are actually weak). More common in children
Rhabdomyolysis (rare)	Severe cases can develop true rhabdomyolysis with massive CK elevation, myoglobinuria, and acute kidney injury

Complication	Pathophysiology
Menorrhagia (most common)	Anovulatory cycles from ↓ GnRH pulsatility. Also ↓ clotting factors ^[1]
Infertility	↑ TRH → ↑ prolactin → suppresses GnRH → hypogonadotrophic hypogonadism. Also: anovulation directly from thyroid hormone deficiency on the ovary
Miscarriage and adverse pregnancy outcomes	Untreated hypothyroidism in pregnancy: ↑ risk of miscarriage, pre-eclampsia, placental abruption, preterm delivery, low birth weight
Impaired fetal neurodevelopment	Maternal T4 crosses the placenta and is critical for fetal CNS development, especially in the first trimester before the fetal thyroid gland is functional. ↓ maternal T4 → ↓ fetal IQ, learning difficulties
Galactorrhoea	↑ TRH → ↑ prolactin → milky nipple discharge

Complication	Pathophysiology
Constipation (very common)	↓ Gut motility due to ↓ metabolic drive to smooth muscle ^[1]
Paralytic ileus	Severe hypothyroidism can cause frank ileus — hypothyroidism is listed as a metabolic cause of paralytic ileus
Pseudo-obstruction (Ogilvie-like)	↓ Autonomic drive to the colon. Hypothyroidism is a recognised metabolic cause of colonic pseudo-obstruction
Ascites	Rare; mechanism similar to effusions (↑ capillary permeability + GAG deposition). Can be exudative or transudative

Complication	Pathophysiology
Pleural effusion	Same mechanism as pericardial effusion — ↑ capillary permeability + ↓ lymphatic drainage + GAG deposition ^[1]. Usually bilateral and transudative
Hypoventilation	↓ Central respiratory drive + respiratory muscle weakness (myopathy affecting diaphragm and intercostal muscles) + possible airway narrowing from macroglossia and pharyngeal myxoedema
Obstructive sleep apnoea	Macroglossia and pharyngeal mucosal oedema (GAG deposition) → upper airway narrowing. Also: obesity contributes

If untreated in the neonatal period → cretinism ^[1]:

Short stature — T3/T4 are essential for GH secretion and bone maturation (growth plate chondrocyte proliferation)
Mental retardation — thyroid hormones are critical for CNS myelination, synaptogenesis, and neuronal migration in the first 2–3 years of life. Damage is irreversible if not treated within the first few weeks
Puffy face — myxoedematous infiltration
Deaf mutism — cochlear development requires thyroid hormones
Protuberant abdomen and umbilical hernia — hypotonia of abdominal muscles

Why Is Neonatal Screening So Important?

The brain develops explosively in the first 2–3 years of life. Thyroid hormones drive myelination of CNS axons, neuronal migration, and synaptogenesis. Without T4, these processes are irreversibly impaired. The tragedy of cretinism is that it is completely preventable with early T4 replacement (within the first 2 weeks of life). This is why Hong Kong has universal neonatal TSH screening.

B. Myxoedema Coma — The Most Severe Complication

This deserves special attention as it is the most life-threatening complication of hypothyroidism.

General features: severe hypothyroidism with hypothermia, respiratory failure with hypoxia, and coma ^[1]

Mortality: 20–60% even with treatment.

Represents the decompensation of all the chronic metabolic effects of hypothyroidism
Usually occurs in patients with longstanding untreated or undertreated hypothyroidism, triggered by a precipitating event

Infection (most common — especially pneumonia, UTI)
Cold exposure (winter months)
Sedatives and opioids (further depress CNS and respiratory drive)
Non-compliance with levothyroxine
Surgery, trauma
Stroke, GI haemorrhage, heart failure

Feature	Mechanism
Hypothermia (core temp often < 35°C, can be < 30°C)	↓ BMR → ↓ thermogenesis. The body cannot generate enough heat
Altered consciousness → coma	↓ CNS metabolic rate + hyponatraemia + hypoglycaemia + hypoxia/hypercapnia all contribute to encephalopathy
Bradycardia and hypotension	↓ Chronotropy + ↓ inotropy + ↓ intravascular volume
Hypoventilation with CO₂ retention	↓ Respiratory drive + respiratory muscle weakness
Hyponatraemia	↑ ADH + ↓ free water clearance
Hypoglycaemia	↓ Gluconeogenesis + possible concurrent adrenal insufficiency
Pericardial/pleural effusions	Chronic accumulation from GAG deposition
Generalised myxoedema	Non-pitting oedema from GAG accumulation

General management:

Treatment of precipitating causes
Maintenance of body temperature (passive rewarming)
Correction of hypoglycaemia with D10
Correction of fluid and electrolytes with NS ± vasopressors
Mechanical ventilation for hypoventilation

Medical treatment:

Liothyronine (T3) — faster onset
Levothyroxine (T4) — IV loading dose (200–500 mcg) then 50–100 mcg/day IV
Hydrocortisone — empirical 50–100 mg IV q8h (give BEFORE or WITH thyroid hormones)

These are iatrogenic complications — from the treatment itself rather than the disease.

Complication	Mechanism	Detail
Acute adrenal crisis	↑ Metabolic clearance of adrenocortical hormones → ↓ cortisol and aldosterone ^[1]	Contraindicated in patients with adrenal insufficiency without prior cortisol replacement. Starting T4 in a patient with undiagnosed Addison's disease or panhypopituitarism → Addisonian crisis (hypotension, hypoglycaemia, shock, death) ^[1]
Deterioration of CVS disease	↑ Workload of heart and worsens ischaemic symptoms ^[1]	Angina / Arrhythmias / Cardiac failure — if T4 is started at too high a dose or titrated too rapidly in elderly or IHD patients, the sudden increase in metabolic rate and myocardial O₂ demand can precipitate acute coronary syndrome or arrhythmia ^[1]
Atrial fibrillation	Chronic over-suppression of TSH (< 0.1 mU/L) → iatrogenic subclinical thyrotoxicosis	3× increased risk of AF if TSH chronically suppressed. Particularly relevant in thyroid cancer patients on TSH-suppressive T4 therapy ^[12]
Osteoporosis	Chronic TSH suppression → ↑ bone turnover → net bone resorption	Especially in post-menopausal women on long-term suppressive T4. Osteoporosis → calcium supplements required ^[10]. Monitor with DEXA scans
Over-replacement symptoms	Iatrogenic thyrotoxicosis	Tremor, palpitations, weight loss, heat intolerance, diarrhoea, insomnia — essentially creating the opposite condition

The Balancing Act in Thyroid Cancer Patients

In thyroid cancer, levothyroxine serves a dual purpose: replacement AND suppression of TSH (to reduce tumour growth). But suppressive doses carry risks of AF and osteoporosis. Modern guidelines stratify this:

Low risk: TSH 0.5–2.0 mIU/L (no suppression needed) ^[12]
Intermediate risk: TSH 0.1–0.5 mIU/L ^[12]
High risk: TSH < 0.1 mIU/L ^[12]

The key is: only suppress as much as the risk warrants. The low risk group does NOT require TSH suppression ^[12].

Many patients become hypothyroid because of treatment for another thyroid condition (surgery, RAI). The complications of these treatments are often encountered alongside hypothyroidism management.

This is extensively tested in exams. Even though these are "surgical complications," they are inseparable from the hypothyroidism story because thyroidectomy is one of the most common causes of hypothyroidism in Hong Kong.

Classification	Complication	Pathophysiology / Detail
Immediate (Intraoperative)	Intraoperative bleeding	Thyroid is a highly vascularised organ (superior and inferior thyroid arteries) ^[10]
	Oesophageal injury	Posterior relation of the thyroid ^[10]
	Tracheal injury	Intimate anterior relation ^[10]
	Tracheomalacia	Floppy tracheal wall due to chronic compression — if a large goitre has been compressing the trachea for years, the tracheal cartilage softens. When the goitre is removed, the trachea may collapse ^[2]^[10]
	Thyroid storm	Only in thyrotoxic patients who are not adequately prepared pre-operatively. Precipitated by surgery in patients with longstanding untreated hyperthyroidism ^[10]
	Superior laryngeal nerve (SLN/EBSLN) injury	SLN supplies the cricothyroid muscle which lengthens (tenses) the vocal cord to produce high-pitched sound. Presents with vocal fatigue and changes in voice quality ^[10]. Loss of high pitch, poor volume, easy fatigue ^[2]
	Recurrent laryngeal nerve (RLN) injury	RLN supplies all intrinsic muscles of larynx except cricothyroid ^[10]
		Ipsilateral (unilateral) RLN injury → unilateral vocal cord palsy → hoarseness and ineffective cough ^[10]
		Bilateral RLN injury → bilateral vocal cord palsy → stridor and dyspnoea (airway obstruction) — because 6 adductors > 2 abductors (the adductors overpower the abductors, pulling both cords to the midline and obstructing the airway) ^[2]^[10]
		↑ Risk of aspiration pneumonia ^[10]
Early	Haematoma formation	Reactionary bleeding within first 24 hours → haematoma compresses on venous return → laryngeal oedema → complete closure of vocal cords → asphyxiation ^[2]
		Management: Remove all stitches from skin down to cervical fascia at bedside (first action!). Resuscitation: protect airway, give supplemental oxygen. Arrange emergency OT for haemostasis ^[2]
		Potentially fatal if compression on airways ^[10]
	Wound infection	NOT a recognised complication (clean surgical field) ^[2] — this is a favourite exam trick question
	Hoarseness of voice (HOV)	Transient HOV: due to vocal cord oedema from endotracheal intubation → resolves spontaneously ^[2]
		Persistent HOV: RLN injury ^[2]
Late	Hypothyroidism	Expected after total thyroidectomy (100%). 10–20% after hemithyroidectomy ^[3]. Late complication requiring lifelong T4 replacement ^[2]
	Hypoparathyroidism → Hypocalcaemia	MOST common complication of thyroidectomy (especially total) ^[10]^[2]
		Only in total thyroidectomy — because all four parathyroid glands are at risk ^[2]
		Usually transient — due to surgical handling/devascularisation of parathyroids, recovers in days to weeks ^[2]
		S/S: perioral numbness, carpopedal spasm, Chvostek's sign, Trousseau's sign ^[2]
		Severe hypocalcaemia can lead to laryngospasm requiring emergency intubation / surgical airway ^[2]
		Management: Ca + vit D supplement (acute: IV Ca gluconate) ^[2]. Specifically: IV 10–20 mL of 10% calcium gluconate over 10 minutes (slow bolus) for acute symptomatic hypocalcaemia. Maintenance: calcium carbonate + calcitriol (vitamin D) ^[10]
	Hungry bone syndrome	Severe and prolonged hypocalcaemia despite normal or even elevated PTH levels ^[10]. Occurs when thyroidectomy is performed for hyperthyroid patients with significant bone disease — sudden removal of PTH/thyroid hormone effect → rapid influx of calcium into "hungry" demineralised bones → profound hypocalcaemia. Associated with hypophosphataemia and hypomagnesaemia ^[10]
	Recurrence (of goitre/nodule)	Only relevant to hemithyroidectomy or subtotal thyroidectomy. Total thyroidectomy has no recurrence risk ^[10]
	Hypertrophic scar / Keloid	Wound complications. Hypertrophic / keloid scar ^[2]

Post-Operative Dyspnoea After Thyroidectomy — Critical DDx

If a patient develops dyspnoea after thyroidectomy, consider these causes in order of urgency ^[2]:

Haemorrhage → haematoma → laryngeal oedema → airway obstruction. Open the wound at bedside immediately
Bilateral RLN irritation → airway obstruction (adductors > abductors)
Laryngeal spasm due to hypocalcaemia → emergency intubation
Injury to trachea / pneumothorax
Tracheomalacia (floppy tracheal wall due to chronic compression by a large goitre)

This is a high-yield exam scenario. The first action for suspected haematoma is open the wound at bedside — do NOT wait for theatre.

RAI is commonly used for Graves' disease and differentiated thyroid cancer. Its main complication:

Complication	Detail
Hypothyroidism	The expected and intended outcome for Graves' disease. Risk of hypothyroidism: 10–15% in first 2 years, then 3% per year onwards ^[14]. Requires lifelong T4 replacement ^[1]
Transient thyroiditis	Radiation-induced inflammation → pain, transient thyrotoxicosis (release of preformed hormone)
Salivary gland damage (sialadenitis)	Salivary glands also concentrate iodine via NIS → radiation damage → dry mouth. Reduce risk with sialogogues (lemon drops, chewing gum)
No effect on fertility, congenital malformations, or cancer risk of offspring ^[1]	Important reassurance for patients
Teratogenic in pregnancy	Contraindicated in pregnancy and lactation — damage to thyroid gland of fetus ^[1]. Avoid breast-feeding since it is secreted in breastmilk ^[1]

Because the most common cause of hypothyroidism in Hong Kong is Hashimoto's thyroiditis, patients are at risk of other autoimmune conditions:

Associated Condition	Prevalence with Hashimoto's	Significance
Type 1 Diabetes Mellitus	~5–10%	Screen with HbA1c/fasting glucose
Addison's disease (autoimmune adrenal insufficiency)	~1–2%	Critical to identify BEFORE starting T4 (risk of adrenal crisis)
Pernicious anaemia	~5–10%	B12 deficiency → macrocytic anaemia, subacute combined degeneration of the cord
Vitiligo	~7%	Autoimmune destruction of melanocytes
Coeliac disease	~2–5%	Causes malabsorption → may ↓ T4 absorption → patient needs higher T4 dose and seems "resistant" to treatment
Primary biliary cholangitis (PBC)	~10–15% have Hashimoto's	T-lymphocyte-mediated attack on intrahepatic bile ducts. Extreme female predominance ^[15]
Thyroid lymphoma	Rare but important	Hashimoto's thyroiditis is a risk factor for primary thyroid lymphoma (MALT or DLBCL). Suspect if a patient with Hashimoto's develops a rapidly enlarging, firm thyroid mass

These associations form part of the autoimmune polyglandular syndromes (APS). APS Type 2 (Schmidt syndrome) is the most relevant: Addison's + autoimmune thyroid disease + T1DM.

High Yield Summary

Complications of untreated hypothyroidism — by system:

CVS: Accelerated atherosclerosis (↓ LDL receptors → hypercholesterolaemia), diastolic HTN (↑ SVR), pericardial effusion, bradycardia, heart failure
Neuro: Depression, cognitive decline ("pseudodementia"), psychosis ("myxoedema madness"), carpal tunnel syndrome, peripheral neuropathy
Haem: Multifactorial anaemia (ACD, iron deficiency from menorrhagia, folate deficiency from bacterial overgrowth, pernicious anaemia from autoimmune gastritis)
Metabolic: Hypercholesterolaemia, hyponatraemia (↑ ADH), hypoglycaemia, elevated CK
Reproductive: Menorrhagia, infertility (↑ prolactin), adverse pregnancy outcomes, impaired fetal neurodevelopment
Respiratory: Pleural effusion, hypoventilation, OSA
GI: Constipation → ileus → pseudo-obstruction
Neonatal: Cretinism (irreversible mental retardation, short stature, deaf mutism)

Myxoedema coma: Most severe complication. Hypothermia + coma + CVS collapse. Mortality 20–60%. Treat with IV T4 ± T3 + IV hydrocortisone + supportive care. Precipitants: infection, cold, sedatives, non-compliance.

Treatment complications:

Adrenal crisis (if coexisting adrenal insufficiency not treated first)
CVS deterioration (angina, arrhythmias, HF — if started too fast in elderly/IHD)
AF and osteoporosis (from chronic TSH over-suppression)

Thyroidectomy complications: Haematoma (open wound at bedside!), RLN injury (unilateral → hoarseness; bilateral → airway obstruction), EBSLN injury (voice quality), hypoparathyroidism (MOST common — perioral numbness, carpopedal spasm; treat with IV Ca gluconate acutely), tracheomalacia, hypothyroidism. Wound infection is NOT a recognised complication.

Autoimmune associations: T1DM, Addison's, pernicious anaemia, vitiligo, coeliac disease, PBC, thyroid lymphoma.

Active Recall - Complications of Hypothyroidism

References

^[1] Senior notes: felixlai.md (Hypothyroidism: Clinical Features, Treatment, Myxoedema Coma, Causes, Anaemia mechanisms) ^[2] Senior notes: maxim.md (Thyroidectomy complications: haematoma, RLN/EBSLN injury, parathyroid injury, post-op dyspnoea DDx, wound complications) ^[3] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (Surgical treatment of benign nodules, hypothyroidism rates) ^[10] Senior notes: felixlai.md (Thyroid cancer: Complications of thyroidectomy, Hypoparathyroidism, Hungry bone syndrome, T4 replacement post-thyroidectomy) ^[12] Senior notes: maxim.md (Thyroxine roles and TSH suppression targets, Thyroidectomy indications and pre-op evaluation) ^[14] Senior notes: felixlai.md (Treatment of hyperthyroidism comparison table: surgery vs anti-thyroid drugs vs RAI, risk of hypothyroidism) ^[15] Senior notes: felixlai.md (Primary biliary cholangitis: associated medical conditions including Hashimoto's thyroiditis)