Hypothyroidism

Meet the patient

A 54-year-old woman presents over six months of cold intolerance, a stone of weight gain despite a poor appetite, constipation she blames on "getting older", and menorrhagia. Her GP checked a TFT for "tiredness" and the TSH came back at 28 mIU/L. Her heels are puffy, her voice has gone croaky, and her ankle jerk hangs in the air for a full second before it relaxes.^[1][2]

Two exam questions are now live on her: where is the defect — thyroid, pituitary, or hypothalamus? and what is the single most sensitive test that proves it? Everything below answers those two questions at consultant depth, then carries you all the way to myxoedema coma.^[1]

One hormone, one axis, three faces

Hypothyroidism is thyroid hormone deficiency at the tissue level — and because thyroid hormone acts on nearly every organ, the presentation is gloriously non-specific. Fatigue, constipation, menorrhagia, weight gain, depression, hyponatraemia, hyperlipidaemia, anaemia, unexplained bradycardia — hypothyroidism walks into every one of those differentials.^[2]

The condition sits on a spectrum, and the spectrum decides everything you do: subclinical (a biochemical abnormality without symptoms) at one end, overt (symptomatic hormone deficiency) in the middle, and myxoedema coma (the decompensated, life-threatening extreme) at the other.^[2][7]

Two words juniors blur — separate them once and they stay:^[1]

• Myxoedema is the non-pitting, doughy soft-tissue infiltration from hydrophilic glycosaminoglycans (chiefly hyaluronic acid and chondroitin sulfate) accumulating in the dermis. It is a sign of severe, long-standing disease — not a synonym for hypothyroidism itself, even though "myxoedema" was historically used that way.
• Myxoedema coma is the life-threatening decompensation — altered mental status plus decompensated hypothyroidism plus a precipitant, typically with hypothermia, hypoventilation, bradycardia and hyponatraemia.^[7][8]

Etymology for viva gold: myxoedema is from the Greek myxa (mucus) and oidema (swelling) — the mucinous swelling. William Ord coined the word in 1877 when he autopsied women with this doughy infiltration and a shrunken thyroid. The metaphor is long dead; the pathology it named is exactly what you will see on the ward.^[1]

Why TSH alone screens, but TSH + free T4 localises

A normal TSH, in a patient with an intact pituitary, effectively excludes primary thyroid disease. That single sentence is why TSH is the front-door screening test. The negative-feedback loop between free T4 and TSH is so steep that a tiny fall in free T4 produces a measurably raised TSH long before symptoms appear.^[2]

But TSH alone tells you the gland is failing — it does not tell you where the failure is. Add free T4, and the pattern localises the defect in one read:^[2][3]

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The teaching pattern that earns marks in every stem:^[1]

^[1]

The classic trap — and the one that costs the most marks: a "normal" TSH with a low free T4 is NEVER normal. In central disease the thyroid is intrinsically healthy but under-stimulated, so TSH does not rise appropriately. If you stop at the TSH, you miss a pituitary macroadenoma and you precipitate adrenal crisis by giving levothyroxine to a cortisol-deficient patient. Always request a free T4 when central disease is on the cards.^[1]

A goitre adds a second clue. Goitrous disease (Hashimoto early, iodine deficiency, dyshormonogenesis) means the gland is being driven hard by TSH but cannot make enough hormone; atrophic or non-goitrous disease (Hashimoto late, post-ablative, iatrogenic, central) means there is no TSH drive to begin with.^[1]

How common, who, and which cause

Overt hypothyroidism affects roughly one in 300 people in the United States (about 1 per cent of Chinese adults in a nationwide survey), with a higher prevalence among women and older patients; subclinical disease is commoner still — about 4 to 8.5 per cent, and up to 20 per cent in women older than 60.^[10][17][16]

^{[10] [16] [5] [26] [11]}

The cause flips with geography. Worldwide, iodine deficiency dominates — it blights roughly 2 billion people and remains the commonest preventable cause of intellectual disability. In iodine-sufficient regions (most of North America, much of Europe, urban India post-iodisation), chronic autoimmune (Hashimoto) thyroiditis is the runaway leader.^[2]

Host risk factors to reel off on autopilot: female sex, age over 60, a personal or family history of autoimmune disease (type 1 diabetes, coeliac, Addison, vitiligo, alopecia, pernicious anaemia, rheumatoid, lupus), the chromosomal syndromes (Turner, Down, Klinefelter), the postpartum period, prior thyroid disease or treatment, and iodine intake that is either deficient or excessive.^[1][2]

Iatrogenic and drug causes are an examiner staple — name the drug and its mechanism:^[2]

• Amiodarone — 15 to 20 per cent of treated patients develop some form of thyroid dysfunction. Amiodarone-induced hypothyroidism is commoner in iodine-sufficient areas and in patients with previously diagnosed Hashimoto thyroiditis; it is treated with levothyroxine, and the amiodarone often need not be stopped. The drug also causes thyrotoxicosis (type 1 in underlying thyroid disease, type 2 as a destructive thyroiditis treated with glucocorticoids).
• Lithium — has adverse effects on the thyroid; lithium-induced hypothyroidism is relatively common but easily diagnosed and treated.
• Immune checkpoint inhibitors (with interferon and interleukin-2) — recognised drug causes of hypothyroidism.
• Radioactive iodine and thyroid surgery — frequent, anticipated causes; lifelong replacement follows.^[14][20][2]

Hashimoto — the autoimmune default

If you are in an iodine-sufficient region and the patient is a woman between 30 and 60 with a firm, rubbery, diffuse goitre, the diagnosis is Hashimoto until proven otherwise. It is an organ-specific autoimmune disease, and anti-thyroid peroxidase (anti-TPO) antibodies are its serological hallmark — positive in about 90 per cent.^[1]

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The immunological lesion, in one breath: loss of self-tolerance recruits autoreactive CD4+ T-helper cells (a Th1 cytokine profile — IFN-gamma, TNF-alpha, IL-2), which bring in macrophages and cytotoxic CD8+ T cells. The gland is destroyed by a combination of cytotoxic T-cell killing, antibody-dependent cell-mediated cytotoxicity, complement, and Fas/FasL apoptosis.^[1]

The histology matches: dense lymphocytic infiltration with germinal centres, oxyphil (Hurthle) cell metaplasia of the follicular epithelium, and variable fibrosis. Early disease is goitrous (infiltration outpaces destruction); late disease is atrophic (fibrosis wins). Function declines as follicular mass is lost — subclinical becomes overt over years, faster if anti-TPO positive (about 4 per cent per year).^[1]

Two complications to carry into the viva: a small but real risk of thyroid B-cell lymphoma (a MALT-type lymphoma in longstanding Hashimoto, presenting as a rapidly enlarging asymmetric goitre) and an association with papillary thyroid carcinoma more often than chance.^[1]

Etymology for viva gold: Hashimoto thyroiditis carries the name of Hakaru Hashimoto, the Japanese surgeon who described it in 1912 from four women in Kyushu. His paper was ignored for forty years; the disease is now the commonest cause of hypothyroidism in the developed world. Hurthle cells are the oxyphil metaplasia of the follicular epithelium — Karl Hurthle actually described dog thyroid cells; the human cells were named for him by others, wrongly, and the name stuck.^[1]

The axis, the iodide trap, and why T4 alone is enough

The hypothalamic-pituitary-thyroid axis is a textbook negative-feedback loop, and you must walk it in order at viva. TRH from the hypothalamus drives TSH from the pituitary thyrotrophs; TSH binds the TSH receptor on the follicular cell and fires five jobs in series:^[2]

The thyroid's five-step job — "trap, oxidise, couple, release, convert":^[1]

1. Trap — iodide uptake through the sodium-iodide symporter (NIS), concentrating iodide 20 to 50 times above plasma.
2. Oxidise — thyroid peroxidase (TPO) plus hydrogen peroxide (from DUOX2) oxidises iodide onto tyrosyl residues of thyroglobulin, making monoiodotyrosine (MIT) and di-iodotyrosine (DIT).
3. Couple — TPO links two DITs to make T4, and one MIT plus one DIT to make T3.
4. Release — colloid is endocytosed, thyroglobulin is lysosomally degraded, T4 and T3 enter the blood.
5. Convert — circulating free T4 and free T3 feed back on the pituitary and hypothalamus (after local D2 conversion to T3), shutting off TSH and TRH.^[1]

The single sentence that justifies modern therapy: about 80 per cent of circulating T3 is generated peripherally by deiodination of T4, and only 20 per cent is secreted directly by the thyroid. That is exactly why levothyroxine (T4) alone is adequate replacement for almost every patient — the body makes its own T3 from it. D1 and D2 convert T4 to active T3; D3 inactivates both to reverse T3 and T2.^[1]

Pregnancy, oestrogen, and hepatitis raise thyroxine-binding globulin (TBG), raising total but not free T4 — which is why you must always interpret free T4 in pregnancy, never total. Most circulating T4 and T3 is protein-bound to TBG, transthyretin and albumin; only the free fraction is biologically active.^[1]

From molecule to symptom — the cellular basis

At the molecular level, T3 is a ligand-activated transcription factor that turns up the body's metabolic thermostat. It binds the nuclear thyroid hormone receptor (TR-alpha, TR-beta) and upregulates Na-K-ATPase, beta-adrenergic receptors, malic enzyme and SERCA. In hypothyroidism each dial falls, and each symptom maps onto a dial:^[2]

• Na-K-ATPase falls — basal metabolic rate drops (cold intolerance, weight gain, bradyergia), thermogenesis fails (hypothermia).
• Beta-adrenergic signalling falls — bradycardia, reduced inotropy, low cardiac output, and the diastolic hypertension of raised systemic vascular resistance.
• SERCA falls — diastolic relaxation slows in cardiac and skeletal muscle; the slow-relaxing (hung-up) ankle jerk is born here.
• Glycosaminoglycans accumulate in the dermis — the non-pitting myxoedematous puffiness; the same deposition in the vocal cords gives the hoarse, croaking voice.
• LDL-receptor expression falls — hypercholesterolaemia.
• Free-water clearance falls and ADH is inappropriately high — hyponatraemia.
• Gut motility falls — constipation, rarely myxoedema megacolon.
• TRH rises (loss of feedback) and drives prolactin — galactorrhoea and menstrual disturbance.^[1]

The iodine-deficiency goitre is the same loop running in reverse. Without enough iodide, T4 synthesis falls, the brake on TSH releases, and chronic TSH hyperstimulation drives follicular hypertrophy, hyperplasia and colloid accumulation — the diffuse, soft, symmetric goitre of endemic deficiency. Iodine repletion reverses early goitre and prevents cretinism.^[2]

Central hypothyroidism is upstream failure with an intact gland. The thyroid is healthy, but TSH or TRH drive is lost. Free T4 falls, yet TSH does not rise — it sits low or "normal", which is inappropriately normal for the low free T4. The clues are the coexisting anterior-pituitary deficits (secondary amenorrhoea, hypogonadism, adrenal insufficiency, growth failure), a headache or bitemporal hemianopia from a macroadenoma, and a history of pituitary surgery, radiation, severe postpartum haemorrhage (Sheehan) or infiltrative disease.^[1]

The clinical picture — one sign per system

Hypothyroidism presents insidiously over months, and the symptoms are often blamed on ageing or stress. A TFT checked for an unrelated reason is the commonest route to diagnosis. Cluster the features system by system and the ward round becomes easy.^[2]

General: fatigue, lethargy, somnolence, cold intolerance (the cardinal symptom — feeling cold when others are comfortable), modest weight gain of 2 to 5 kg (fluid and a low metabolic rate, not fat), sluggishness, slowed movement and slowed speech.^[1]

Skin and soft tissues: dry, cool, pale, rough skin; brittle hair and slow-growing nails; thinning of the lateral third of the eyebrow (madarosis); non-pitting myxoedematous puffiness of the periorbital region, hands and feet; macroglossia; broad thickened lips; a hoarse croaking voice. Carotenaemia — yellow-orange palms, soles and nasolabial folds from impaired hepatic beta-carotene conversion — is striking and easily missed. Vitiligo or alopecia areata hint at coexisting autoimmunity.^[1]

Cardiovascular: bradycardia, reduced pulse pressure, often diastolic hypertension; distant heart sounds and mild cardiomegaly from a pericardial effusion (a transudate, usually haemodynamically insignificant). Beware: treating hypothyroidism can unmask angina, because the bradycardia had been lowering myocardial oxygen demand.^[1]

Respiratory: pleural effusions, reduced vital capacity, a depressed respiratory drive, and sleep-disordered breathing or obstructive sleep apnoea (worsened by macroglossia and pharyngeal infiltration).^[1]

Gastrointestinal: constipation (often severe), rarely adynamic ileus or myxoedema megacolon; ascites rarely; gallstones commoner from impaired gallbladder motility; achlorhydria and pernicious anaemia may coexist (autoimmune gastritis).^[1]

Neuromuscular: the slow-relaxing (hung-up) ankle jerk is the classical bedside sign — the reflex fires briskly but the relaxation phase is delayed; muscle aching, stiffness and proximal weakness with a raised creatine kinase; muscle hypertrophy (Hoffmann syndrome) in severe long-standing disease; bilateral carpal tunnel syndrome; sensorineural deafness; cerebellar ataxia rarely; depression, cognitive slowing and poor concentration; rarely psychosis ("myxoedema madness") and seizures.^[1]

Reproductive: menorrhagia, oligomenorrhoea, amenorrhoea, anovulatory infertility; galactorrhoea from TRH-driven hyperprolactinaemia; loss of libido and erectile dysfunction in men. In pregnancy, increased risk of miscarriage, pre-eclampsia, preterm birth and impaired fetal neurodevelopment.^[1]

Haematological and metabolic: normocytic or macrocytic anaemia (the latter from coexisting B12-deficient pernicious anaemia), raised creatine kinase, raised LDL cholesterol, hyponatraemia, hyperprolactinaemia.^[1]

Bedside signs that should trigger the test: periorbital puffiness, slow-relaxing ankle reflexes, bradycardia, cold dry skin, hoarse voice. The apathetic elderly presentation — depression, cognitive decline, falls, failure to thrive, "going off" — is classic signs muted and the diagnosis made on TFT. Confused with dementia until tested.^[1]

What else could it be — discriminators, not lists

The clinical syndrome has a broad differential; the TFT pattern has a narrow one, and it is the one that pays the rent. Run the clinical differential first, then lock the diagnosis with the pattern.^[2][6]

^[1]

The examiner's real differential is the TFT pattern itself. This is the table that wins the long-case stem:^[1]

^[1]

Euthyroid sick syndrome is the trap inside the trap. A critically-ill patient (sepsis, post-op, malignancy, ICU) shows a low or normal TSH with a low free T3 — and sometimes a low free T4 with a high reverse T3. It is an adaptive down-regulation of metabolism (D1 and D2 down, D3 up). It does not need thyroid hormone, and giving levothyroxine for it is a recognised error. It resolves as the underlying illness recovers.^[6]

Myxoedema coma has its own differential — any unexplained hypothermia with reduced consciousness earns a TSH and a free T4, because myxoedema coma is treatable and missing it is fatal. Distinguish it from sepsis (often the precipitant, may coexist), adrenal crisis (may coexist — give hydrocortisone anyway), hypoglycaemia, drug overdose, environmental hypothermia and stroke.^[1]

The bedside round — what the slow ankle jerk buys you

Examination rarely makes the diagnosis; it confirms the clinical suspicion, characterises the goitre, grades the severity, and hunts for associated autoimmune or pituitary disease. Run the thyroid examination in order.^[1][2]

• Inspect from the front — swelling, asymmetry, scars, distended neck veins.
• Ask the patient to swallow a sip of water — a thyroid swelling rises with swallowing, because it is invested in pretracheal fascia.
• Palpate from behind the seated patient with both hands — size, consistency, surface (smooth or nodular), mobility, tenderness, and the lower extent (a goitre descending below the sternoclavicular joint on swallowing is retrosternal).
• Percuss the manubrium for a dull note (retrosternal extension).
• Auscultate for a bruit — a continuous or systolic bruit points to Graves hyperthyroidism from hypervascularity, not Hashimoto.
• Feel the cervical and supraclavicular nodes.^[1]

Characterise the goitre against the cause:^[1]

^[1]

Bedside signs of hypothyroidism to elicit on every long case:^[1]

• Slow-relaxing (hung-up) ankle reflexes — tap the Achilles with the patient kneeling on a chair or the foot dorsiflexed; the reflex fires briskly but relaxes late. This is the sign that pays the rent.
• Bradycardia, diastolic hypertension, distant heart sounds, signs of a pericardial effusion.
• Periorbital and pedal puffiness, cool dry skin, carotenaemia, macroglossia, hoarse voice, slow speech.
• Proximal muscle weakness, thenar wasting and a positive Tinel sign (carpal tunnel).
• In the decompensated extreme: hypothermia, hypoventilation, reduced consciousness.^[1]

Look beyond the thyroid. In suspected autoimmunity, seek vitiligo, alopecia areata, Addison pigmentation; in suspected central disease, confront visual fields (bitemporal hemianopia), check for hypogonadism and a postural drop from ACTH deficiency, and map the other anterior-pituitary axes.^[1]

Investigations — TSH first, free T4 to localise, antibodies to explain

TSH is the single most sensitive first-line test for primary thyroid disease; free T4 is added when TSH is abnormal, when central disease is suspected, or in pregnancy. Free, never total, T4 — because total T4 is confounded by TBG changes in pregnancy, on oestrogen, and in hepatitis or nephrotic syndrome.^[2]

Free T3 is rarely needed in primary disease — reserve it for suspected T3-toxicosis and never use it to monitor routine levothyroxine.^[1]

Antibodies close the aetiological loop:^[1]

• Anti-TPO — the serological marker of Hashimoto (positive in about 90 per cent). It confirms the autoimmune aetiology and predicts progression from subclinical to overt disease (about 4 per cent per year if positive, under 2 per cent if negative).
• Anti-thyroglobulin (anti-Tg) — supportive but less sensitive and specific; also a tumour-marker caveat after thyroid cancer.
• TSH-receptor antibodies (TRAb) — for suspected Graves, not hypothyroidism (though blocking TRAb can cause atrophic thyroiditis, a rare goitre-less primary hypothyroidism).^[1]

Confirm subclinical disease before committing to lifelong therapy. It is defined as a TSH above the reference range (typically over 4.0 to 4.5 mIU/L) with a normal free T4 in a stable, non-pregnant patient — and it must be confirmed by repeating the TFT at 3 months, because transient TSH elevation is common after non-thyroidal illness. Then apply the treatment thresholds (below).^[5][6]

Associated laboratory abnormalities are examiner favourites — name the mechanism, not just the finding:^[1]

• Raised LDL — downregulated LDL receptor.
• Hyponatraemia — impaired free-water clearance plus inappropriate ADH; usually mild.
• Normocytic or macrocytic anaemia — macrocytic means think coexisting B12-deficient pernicious anaemia (autoimmune, associated).
• Raised creatine kinase — from myopathy; can be very high, do not confuse with rhabdomyolysis or MI.
• Raised prolactin — TRH-driven; mild, resolves with replacement.
• Hypoglycaemia, hypocalcaemia, hyperkalaemia — only in severe disease or coexisting adrenal insufficiency.^[1]

Image only when the question demands it. Thyroid ultrasound for a nodular goitre, a rapidly enlarging gland, a dominant nodule or cervical lymphadenopathy (rule out malignancy) — not for routine Hashimoto. Pituitary MRI with contrast when central disease is suspected. Cardiac echo if a pericardial effusion or heart failure is in play.^[1]

Levothyroxine — name the dose, the timing, the recheck

Levothyroxine (T4) is the standard of care — oral, once-daily, cheap, well tolerated, and effective as monotherapy in essentially every patient, because peripheral deiodination supplies the T3.^[3][9]

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The dose depends on who is in front of you. Name the patient, then name the number.^[3]

^{[10] [26] [24] [13]}

How to take it — the three rules that decide whether the dose works:^[15]

• Once daily, on an empty stomach — taking levothyroxine on an empty stomach enhances absorption; levothyroxine is absorbed in the small intestine within about three hours of ingestion, a process dependent on gastric acidity. Night-time administration has shown similar results to morning dosing.
• Separate from interfering foods and drugs by 3 to 4 hours — calcium and iron salts and proton-pump inhibitors impair absorption, as do fibres, espresso coffee and grapefruit juice.
• Mind the gut — Helicobacter pylori infection, atrophic gastritis, coeliac disease and bariatric surgery all alter absorption or requirement.^[15]

Everyone forgets: absorption problems and changing requirement are the usual reasons a TSH drifts on a previously stable dose. Calcium and iron salts and proton-pump inhibitors reduce absorption (separate by 3 to 4 hours); gastrointestinal disease can do the same; and pregnancy raises the requirement — women should increase the weekly dose by about 30 per cent (one extra dose twice a week) once pregnant, followed by monthly evaluation and management. When the TSH climbs on a stable dose, work the list in order: adherence, then pregnancy, then interactions or absorption, then weight change — before assuming autoimmune progression.^[15][10]

Monitoring is a number, not a vibe:^[3]

• Re-check the TSH about two months after starting levothyroxine and make dosage adjustments accordingly; adjust and repeat until stable.
• Once stable, monitor the serum TSH at least annually thereafter, and at any clinical change (pregnancy, new symptoms, new interacting drug, weight change).
• Monitor TSH in primary disease; free T4 in central disease. In secondary hypothyroidism the free T4, with clinical assessment, is the cornerstone for diagnosis and for monitoring treatment — the TSH is unreliable.
• Target the lower half of the reference range — the aim for most adults is a stable serum TSH of about 0.4 to 2.5 mU/L. Avoid over-replacement: a suppressed TSH (under 0.1 mU/L) is associated with atrial fibrillation and reduced bone mineral density.^[5][26][16]

Subclinical hypothyroidism — the threshold question

Subclinical disease is a raised TSH with a normal free T4, confirmed at 3 months, and the only question is whether to treat. The thresholds come straight from the ATA and ETA and are reproduced verbatim.^[5][6]

• TSH over 10 mU/L — treat — replacement therapy with L-thyroxine is recommended for younger patients (under 65 to 70 years) even in the absence of symptoms; most patients with subclinical disease do not benefit from treatment unless the TSH is over 10 mIU/L or the TPO antibody is elevated.^[5][10]
• TSH 4.0 to 10 mU/L — individualise — a trial of L-thyroxine should be considered in younger symptomatic patients; treat regardless of symptoms if the TPO antibody is elevated, and some authorities also treat women planning pregnancy and patients with goitre; review the response 3 to 4 months after the TSH reaches the reference range and generally stop if symptoms have not improved.^[5][10][26]
• In the oldest old (over 80 to 85 years) with TSH of 10 mU/L or less, follow a wait-and-see strategy, generally avoiding hormonal treatment.^[5]

The natural history depends on antibodies and age. An initially raised TSH must be confirmed with a repeat measurement (with FT4 and TPO antibodies) after 2 to 3 months, because transient elevation occurs; subclinical hypothyroidism shows good evidence of progression to overt disease, and women with positive thyroid antibodies are especially at risk. If treatment is not started, monitor — subclinical hypothyroidism may be as prevalent as 20 per cent in older people and rises with age.^[5][16]

Central hypothyroidism — cortisol first, always

In central disease the biochemistry is low or inappropriately normal TSH plus a low free T4 in the context of known or suspected pituitary disease. The gland is fine; the drive is gone.^[1]

Before thyroid hormone, exclude and treat coexisting adrenal insufficiency. Central hypothyroidism is often complicated by coexisting deficits of the other pituitary axes — including ACTH-cortisol — and hydrocortisone should be given with or before the levothyroxine, continuing until adrenal insufficiency has been excluded. Then treat with levothyroxine, monitoring to the free T4.^[22][12][26]

In secondary disease the free T4, together with clinical assessment, is the cornerstone for both diagnosis and treatment monitoring — the TSH is unreliable. Investigate the underlying lesion with pituitary imaging and a full anterior-pituitary work-up, remembering that the several hypothalamus-pituitary axes interact and that dysfunction of one influences the diagnosis and treatment of the others.^[26]

Pregnancy — two extra tablets a week

Pregnancy raises the levothyroxine requirement by 25 to 30 per cent — and under-treating harms two patients at once. The mechanism is a stack: rising oestrogen raises TBG; the placental D3 deiodinase degrades T4 and T3; the fetus demands maternal T4 in the first trimester before its own thyroid functions; and renal iodine clearance rises. The requirement climbs from weeks 4 to 6, peaking at 16 to 20 weeks.^[4]

The action is a number, applied at the pregnancy test: at confirmation, increase the levothyroxine dose by about 25 to 30 per cent — the practical rule is one extra dose twice a week (two extra tablets per week), followed by monthly evaluation and management. Check TSH each trimester and 4 to 6 weeks postpartum, then reduce to the pre-pregnancy dose after delivery.^[4][10]

Trimester-specific TSH targets (ATA 2017), reproduced verbatim:^[4]

• First trimester: under 2.5 mIU/L.
• Second trimester: under 3.0 mIU/L.
• Third trimester: under 3.0 mIU/L.^[1]

Untreated overt hypothyroidism in pregnancy is dangerous: miscarriage, fetal loss and stillbirth; pre-eclampsia, gestational hypertension, placental abruption, anaemia; preterm birth and low birthweight; and impaired fetal neurodevelopment — maternal T4 is essential for early fetal brain development before the fetal thyroid functions at around 12 to 14 weeks, and first-trimester maternal hypothyroidism lowers offspring IQ. Even subclinical disease is associated with adverse outcomes; treat to keep TSH within the trimester-specific reference.^[4]

The screening debate is live and both sides are defensible. The ATA recommends targeted screening (goitre, strong family history, prior thyroid disease, type 1 diabetes, autoimmune disease, infertility, prior preterm delivery, IVF or ICSI, miscarriage, age over 30, BMI over 40, amiodarone or lithium, recent contrast); many European centres screen universally. Hypothyroidism is safe in lactation — levothyroxine crosses minimally into breast milk and is identical to endogenous T4.^[1]

The elderly and the ischaemic heart — start low, go slow

In the elderly or anyone with ischaemic heart disease, the danger is not the disease — it is the treatment given too fast. Presentations are atypical (apathy, depression, cognitive decline, falls, failure to thrive, hyponatraemia, constipation), often mistaken for dementia or normal ageing, so keep a low threshold to test TSH.^[1]

Start low and go slow. In patients over 60, or with known or suspected ischaemic heart disease, start at a lower dosage — 12.5 to 50 mcg daily — rather than full replacement; in a large randomised trial of older adults with subclinical hypothyroidism, the starting dose was 50 mcg daily, or 25 mcg if body weight was under 50 kg or coronary heart disease was present. Rapid replacement can unmask ischaemic heart disease; if angina appears on initiation, reduce the dose and treat the angina first, then re-titrate slowly. Note too that in that trial levothyroxine provided no apparent symptomatic benefit in adults of 65 and over with subclinical disease — test and treat deliberately, not reflexively.^[10][24]

T4 plus T3 — the honest answer

A minority of patients report persistent symptoms — fatigue, low mood, cognitive fog — despite a biochemically normal TSH on levothyroxine monotherapy. Levothyroxine plus liothyronine (T4/T3) combination therapy is the controversial option, and the honest answer is: evidence does not support routine use.^[9]

The 2021 ATA and European Thyroid Association task force concludes there is insufficient evidence for routine combination therapy, but a carefully monitored trial may be considered in symptomatic, biochemically well-replaced patients who have been adequately worked up for alternative causes. It is not recommended in pregnancy, cardiac disease, the elderly, or osteoporosis — and liothyronine (T3) monotherapy is not recommended for routine hypothyroidism.^[9]

Myxoedema coma — the decompensated extreme

Myxoedema coma is an endocrine emergency: decompensated hypothyroidism with altered mental status, hypothermia and respiratory failure, usually after a precipitating event in a patient with longstanding untreated or under-treated disease. It is rare, it is lethal — reported mortality ranges from 20 to 25 per cent to as high as 60 per cent (a comprehensive 2004 to 2024 review found an overall mortality of 38.8 per cent, with shock and multiorgan failure accounting for most deaths) — and it is eminently treatable if you think of it.^[7][8][11]

The diagnosis is clinical; thyroid function tests do not accurately reflect severity. The diagnostic triad:^[7][8][21]

1. Altered mental status — the hallmark clinical feature is progressive deterioration in mental status (confusion, lethargy, obtundation, coma).
2. Decompensated hypothyroidism biochemically — high TSH plus low free T4 in primary disease, or low or normal TSH plus low free T4 in central disease; obtain TSH and free thyroxine when considering the diagnosis.
3. A precipitating event — stressors such as infection frequently disrupt the compensatory mechanisms and precipitate the deterioration, with decompensation features — hypothermia, bradycardia, mixed respiratory failure, hyponatraemia, hypoglycaemia.^[11][21]

The management bundle is applied on suspicion — recognise rapidly, admit to intensive care promptly, and treat.^[11][21]

1. Airway and breathing — patients with suspected myxoedema coma should be admitted to an intensive care unit for vigorous pulmonary and cardiovascular support; mixed respiratory failure with CO2 retention is part of the multi-organ failure picture.
2. Investigate — obtain a thyroid-stimulating hormone and free thyroxine level, with cortisol, and a full septic and metabolic screen, remembering that serum thyroid hormone concentrations do not accurately reflect severity.
3. Early steroid supplementation — hydrocortisone should be administered until coexisting adrenal insufficiency is ruled out; supportive care must cover possible intercurrent illness and adrenal insufficiency.
4. Thyroid hormone replacement — high-dose levothyroxine is typical treatment, given intravenously; most authorities recommend intravenous levothyroxine (T4) as opposed to intravenous liothyronine (T3), with liothyronine added for critically ill patients.
5. Supportive care — cardiovascular, respiratory and thermoregulatory support leads the management alongside the hormone therapy.
6. Treat the inciting event — resuscitation, early steroid supplementation, thyroid hormone replacement, and treatment of the inciting event is the core emergency-department bundle; infection is the classic precipitant.
7. ICU admission — these patients are critically ill and need prompt intensive care admission with ventilatory, cardiovascular and biochemical monitoring.^{[12][21][7][11]}

^{[11] [12] [21] [7]}

The cortisol-first principle generalises beyond myxoedema coma. In any patient with central hypothyroidism or suspected panhypopituitarism — Sheehan syndrome after postpartum haemorrhage, a pituitary macroadenoma, autoimmune polyglandular failure — central disease is often complicated by coexisting pituitary hormone deficits including ACTH-cortisol, and steroid cover should come with or before the thyroid hormone.^[12][22]

Subtypes and scenarios you will meet

Hashimoto thyroiditis is the autoimmune default: a woman of 30 to 60 with a family history of autoimmune disease, gradual hypothyroid symptoms and a firm rubbery diffuse goitre, anti-TPO positive in about 90 per cent. Some present euthyroid or subclinical. Watch for a transient thyrotoxic phase ("hashitoxicosis") from follicular rupture, distinguished from Graves by the absence of TRAb and a low radioactive iodine uptake. Associations are the autoimmune cluster — type 1 diabetes, pernicious anaemia, Addison (Schmidt), vitiligo, alopecia, coeliac, Sjogren, lupus, rheumatoid, Turner and Down. Complications are progressive hypothyroidism, thyroid B-cell lymphoma (MALT) in longstanding disease, and the papillary carcinoma association.^[1]

Post-ablative and iatrogenic disease is anticipated, not unexpected. After radioiodine for Graves, most patients are permanently hypothyroid within 3 to 12 months — preferable to recurrent hyperthyroidism, with lifelong levothyroxine. After thyroidectomy, start lifelong replacement within 24 to 48 hours. After external beam radiotherapy to the neck, monitor TFT annually for late-onset failure.^[1]

Drug-induced disease — amiodarone (check TFT before and every 6 months; hypothyroidism commoner in iodine-sufficient regions and anti-TPO-positive patients, treated with levothyroxine while the cardiac indication continues; amiodarone-induced thyrotoxicosis type 2 is a destructive thyroiditis treated with steroids); lithium (check at baseline and 3 to 6 months, treat with levothyroxine if hypothyroid, lithium need not always stop); immune-checkpoint inhibitors, interferon, interleukin-2 (painless thyroiditis with a thyrotoxic then hypothyroid phase — beta-blockers in the thyrotoxic phase, levothyroxine in the hypothyroid).^[1]

Subacute (de Quervain) and postpartum thyroiditis both run a thyrotoxic phase into a transient hypothyroid phase. De Quervain is viral, painful and tender with a raised ESR and CRP — NSAIDs and beta-blockers for the thyrotoxic phase, levothyroxine if symptomatic and hypothyroid, often tapered after 3 to 6 months. Postpartum thyroiditis is painless, occurs within a year of delivery in 5 to 10 per cent of women (often anti-TPO positive), with a thyrotoxic phase at 1 to 3 months (often mislabelled postpartum depression or anxiety) then a hypothyroid phase at 4 to 8 months — treat the hypothyroid phase with levothyroxine if symptomatic, taper postpartum; recurrence is high in subsequent pregnancies and 20 to 40 per cent progress to permanent hypothyroidism.^[1]

Congenital hypothyroidism (cretinism) is detected by newborn screening — primary TSH-based screening has become standard in many parts of the world, and its benefits by heel-prick TSH are well documented and justify universal application. Unrecognised, it leads to mental retardation; screening plus thyroid therapy started within 2 weeks of age can normalise cognitive development, and the recommended initial levothyroxine dose is 10 to 15 mcg/kg per day. Primary congenital hypothyroidism — the commonest neonatal endocrine disorder — divides into thyroid dysgenesis (a spectrum of thyroid developmental abnormalities) and dyshormonogenesis (a defective molecular pathway for thyroid hormonogenesis in a structurally intact gland, often goitrous); central congenital hypothyroidism is rarer, caused by hypothalamic or pituitary pathology, and evades TSH-based screening because TSH is not elevated. Delayed treatment may result in profound neurodevelopmental delay — which is exactly what screening exists to prevent.^[13][23][25]

Etymology for viva gold: cretin comes from the French chrétien, "Christian" or "God's creature" — the historic, pitying Alpine term for the child with congenital hypothyroidism. The word is offensive now; the preventable tragedy it named is exactly what newborn screening exists to abolish.^[1]

How patients come to harm — the preventable list

• Missing central hypothyroidism — reading an "in-range" TSH as normal when the free T4 is low; in secondary disease the free T4, with clinical assessment, is the cornerstone of diagnosis.^[26]
• Giving thyroid hormone before steroid cover in panhypopituitarism or myxoedema coma — hydrocortisone should be given until adrenal insufficiency is excluded.^[12][22]
• Mislabelling euthyroid sick (non-thyroidal illness) syndrome as hypothyroidism and treating it — it occurs in about 70 per cent of ICU admissions, appears to be an adaptive response to reduce energy expenditure, and current guidelines do not recommend treating it.^[18][19]
• Under-dosing in pregnancy — the weekly requirement rises by about 30 per cent; guidelines argue for early detection and treatment of hypothyroidism in pregnancy to prevent obstetric complications and potential neurocognitive disorders in the offspring.^[10][25]
• Precipitating angina on initiation in ischaemic heart disease by starting at full dose — start at 12.5 to 50 mcg daily if over 60 or cardiac disease is known or suspected.^[10]
• Over-treatment (a suppressed TSH, under 0.1 mU/L) — associated with atrial fibrillation and reduced bone mineral density.^[16]
• Missing absorption interactions (calcium and iron salts, proton-pump inhibitors, espresso coffee) as the cause of a rising TSH on a previously stable dose — separate intake by 3 to 4 hours.^[15]
• Failing to recognise myxoedema coma as a treatable cause of altered mental status with hypothermia — reported mortality 20 to 60 per cent.^[11]
• Missing a rapidly enlarging, asymmetric goitre in longstanding Hashimoto — a relationship between Hashimoto's and malignant transformation has been proposed; evaluate any rapid change promptly.^[1]

Prognosis and disposition

Treated primary hypothyroidism has an excellent prognosis — normal life expectancy and quality of life, and pregnancy outcomes equivalent to the euthyroid population. Replacement is lifelong for permanent causes (autoimmune, iatrogenic, congenital); thyroiditis-related hypothyroidism may be transient and can be weaned after 3 to 6 months under TFT monitoring.^[2][3]

Myxoedema coma carries high mortality despite appropriate treatment — reported rates range from 20 to 25 per cent to as high as 60 per cent, with an overall pooled mortality of 38.8 per cent in a 2004 to 2024 review, where shock and multiorgan failure accounted for most deaths. Survivors need lifelong levothyroxine.^[11]

Monitoring cadence: re-check the serum TSH about two months after starting levothyroxine (and after dose adjustments), then at least annually once stable; in pregnancy, monthly evaluation and management once the dose is increased.^[5][10]

Refer to endocrinology for central hypothyroidism, pregnancy (planning, pregnant, postpartum thyroiditis), myxoedema coma (ICU with endocrine input), children and congenital disease, refractory biochemistry (rising TSH despite escalating doses, persistent symptoms despite biochemical euthyroidism, suspected malabsorption), coexisting adrenal insufficiency, a rapidly enlarging or asymmetric goitre or cervical lymphadenopathy, and amiodarone-induced thyroid dysfunction.^[1]

Evidence, guidelines and regional differences

ATA 2014 treatment guidelines anchor the US answer: levothyroxine should remain the standard of care for treating hypothyroidism, and the task force found no consistently strong evidence for the superiority of alternative preparations — levothyroxine-liothyronine combination therapy or thyroid extracts — over levothyroxine monotherapy in improving health outcomes. The practical dosing numbers come from primary-care syntheses: start at 1.5 to 1.8 mcg/kg/day in most adults, and at a lower dosage (12.5 to 50 mcg daily) in patients over 60 or with known or suspected ischaemic heart disease.^[3][10]

ETA 2013 subclinical hypothyroidism guideline anchors the European answer: consider subclinical hypothyroidism in two categories — mildly increased TSH (4.0 to 10.0 mU/L) and more severely increased TSH (over 10 mU/L); investigate an initially raised TSH with a repeat TSH and FT4 (with TPO antibodies) after 2 to 3 months; recommend L-thyroxine even without symptoms for younger patients (under 65 to 70 years) with TSH over 10 mU/L, and consider a trial for younger symptomatic patients with TSH under 10 mU/L; review the response 3 to 4 months after the TSH reaches the reference range and generally stop L-thyroxine if symptoms have not improved; follow the oldest old (over 80 to 85 years) with TSH of 10 mU/L or less with a wait-and-see strategy; re-check TSH 2 months after starting treatment and monitor at least annually, aiming for the lower half of the reference range (0.4 to 2.5 mU/L).^[5]

ATA 2017 pregnancy and postpartum guideline sets the trimester-specific TSH targets (under 2.5 mIU/L first trimester; under 3.0 second and third), the 25 to 30 per cent dose increase at confirmation, targeted case-finding screening, and treatment of overt and symptomatic subclinical disease.^[4]

Combination therapy evidence (ATA and ETA 2021 consensus) — a monitored trial of T4 and T3 combination may be considered in well-replaced symptomatic patients, but evidence does not support routine use; not recommended in pregnancy, cardiac disease, osteoporosis, or the elderly.^[9]

Regional picture: in India and the developing world, iodine deficiency remains the dominant cause despite the National Iodine Deficiency Disorders Control Programme and universal salt iodisation, while autoimmune disease rises in urban populations as iodine intake improves; subacute (de Quervain) thyroiditis is relatively common, and herbal or ayurvedic preparations with undisclosed iodine can precipitate or worsen disease. In iodine-sufficient regions (North America, much of Europe), autoimmune Hashimoto dominates and iodine excess (contrast, supplements) is a commoner cause than deficiency.^[1]

Controversies to handle calmly: universal versus targeted screening in pregnancy (both defended; ATA favours targeted, many European centres screen universally); T4 and T3 combination therapy (popular with patient-advocacy groups, evidence weak for routine use); and the upper limit of the TSH reference range (some advocate lowering it to 2.5 to 3.0 mIU/L given the skewed distribution, which would label many more people hypothyroid — mainstream practice keeps the population-derived range of about 0.4 to 4.5 mIU/L).^[1]

The mantra

TSH screens, free T4 localises, anti-TPO explains — and cortisol always comes first.^[1]

^{[1] [1] [2] [26] [10] [15] [5] [11] [12] [14] [1] [1] [11] [12] [21] [22] [10] [1]}

Ward-round test — three stems, thirty seconds each

Stem 1 — the tired, cold, constipated woman (answer)ShowHide

A 54-year-old woman has a TSH of 28 mIU/L, a free T4 below the reference range, a firm diffuse goitre, and a slow-relaxing ankle jerk. What is the diagnosis, the single most useful additional test, and the first prescription? Model: Primary overt hypothyroidism — almost certainly Hashimoto thyroiditis (the commonest cause) given the firm diffuse goitre; Hashimoto is characterised by thyroid-specific autoantibodies, so confirm the aetiology with anti-TPO. Start levothyroxine at 1.5 to 1.8 mcg/kg/day, taken on an empty stomach and separated from calcium and iron salts and PPIs by 3 to 4 hours, and re-check the TSH about two months after starting (aim: lower half of the reference range, 0.4 to 2.5 mU/L). Counsel that replacement is usually lifelong and that if she becomes pregnant she should increase the weekly dose by about 30 per cent — one extra dose twice a week.^{[2][1][10][15][5]}

Stem 2 — the 'normal' TSH that is not normal (answer)ShowHide

A 60-year-old man on the neurosurgery ward two days after a transsphenoidal resection of a pituitary macroadenoma has a free T4 below the reference range and a TSH of 1.2 mIU/L (mid-reference). The house officer plans to start levothyroxine. What is wrong with that plan? Model: This is central hypothyroidism — the TSH is inappropriately normal for the low free T4, which is exactly what you expect after pituitary surgery; in secondary disease the free T4, with clinical assessment, is the cornerstone of diagnosis and monitoring. Central hypothyroidism is often complicated by coexisting deficits of the other pituitary axes — so check cortisol and give hydrocortisone with or before the levothyroxine, then start levothyroxine and monitor to the free T4, because TSH is unreliable in central disease.^[26][22]

Stem 3 — the cold, slow woman on the medical ward (answer)ShowHide

A 78-year-old woman is brought in confused, with a core temperature of 32 degrees C, a heart rate of 38, a sodium of 120, and a CO2 of 8 kPa. She has a history of Hashimoto thyroiditis and ran out of levothyroxine three weeks ago. What is this, and what do you do in the next 30 minutes? Model: Myxoedema coma (decompensated hypothyroidism) — altered mental status with hypothermia, bradycardia and mixed respiratory failure, precipitated here by lapsed levothyroxine. Manage on suspicion and simultaneously: resuscitation, early steroid supplementation (hydrocortisone until adrenal insufficiency is excluded), thyroid hormone replacement with high-dose IV levothyroxine — the route most authorities prefer over IV liothyronine — and treatment of the inciting event, with prompt intensive care admission for vigorous pulmonary and cardiovascular support, obtaining TSH and free T4 (with cortisol and a full septic screen) along the way. Reported mortality ranges from 20 to 25 per cent to as high as 60 per cent.^[21][12][11]

References28ShowHide

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