Hypothyroidism

Hypothyroidism is a clinical syndrome of thyroid hormone deficiency, one of the commonest endocrine disorders worldwide and a perennial NEET PG favourite. These notes cover the primary–secondary divide, Hashimoto thyroiditis, the dosing of levothyroxine, the emergency of myxoedema coma, and the screening logic for congenital and subclinical disease.

Definition & Classification

Hypothyroidism = deficient action of thyroid hormone at tissue level, almost always due to underproduction of T4/T3. It is classified by the anatomical level of the defect along the hypothalamo–pituitary–thyroid (HPT) axis.

Type	Defect site	TSH	Free T4	Classic cause
Primary	Thyroid gland	High	Low	Hashimoto, iodine deficiency, post-thyroidectomy/RAI
Secondary (central)	Anterior pituitary	Low/inappropriately normal	Low	Pituitary tumour, Sheehan, hypophysitis
Tertiary	Hypothalamus (TRH)	Low/normal	Low	Hypothalamic tumour, infiltration, radiation
Peripheral resistance	Thyroid hormone receptor	High/normal	High	Resistance to thyroid hormone (THRB mutation)

High-yield: The single most useful screening test is TSH. A high TSH with low free T4 = primary hypothyroidism (>95% of all cases). A low/normal TSH with low free T4 = central (secondary/tertiary) hypothyroidism.

Worldwide the commonest cause is iodine deficiency; in iodine-replete regions (and the typical exam answer for an adult in a non-endemic area) it is chronic autoimmune (Hashimoto) thyroiditis.

Etiology

Primary hypothyroidism causes:

• Autoimmune — Hashimoto thyroiditis (goitrous) and atrophic thyroiditis (non-goitrous).
• Iatrogenic — post-thyroidectomy, post-radioiodine (RAI) for Graves, external neck irradiation.
• Iodine — deficiency (endemic goitre/cretinism) OR excess (Wolff–Chaikoff effect, e.g. amiodarone, contrast, kelp).
• Drugs — amiodarone, lithium, interferon-α, tyrosine kinase inhibitors (sunitinib), checkpoint inhibitors, antithyroid drugs.
• Infiltrative — Riedel thyroiditis, amyloidosis, haemochromatosis.
• Transient — subacute (de Quervain) and silent/postpartum thyroiditis pass through a hypothyroid phase.

Congenital — thyroid dysgenesis (agenesis/ectopia, ~85%, the commonest cause overall) and dyshormonogenesis (e.g. Pendred syndrome = organification defect + sensorineural deafness, due to SLC26A4/pendrin).

High-yield: Amiodarone (37% iodine by weight) can cause both hypo- (type, especially in autoimmune-prone patients) and hyperthyroidism. Lithium blocks thyroid hormone release and causes goitrous hypothyroidism.

Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)

The prototype autoimmune hypothyroidism — heavily tested.

• Epidemiology: Female:male ≈ 7–10:1; peak 30–50 years. Associated with HLA-DR3/DR5 and other autoimmune disease (T1DM, vitiligo, pernicious anaemia, Addison, coeliac — part of APS-2/Schmidt syndrome).
• Antibodies: Anti-thyroid peroxidase (anti-TPO/antimicrosomal) is the most sensitive and characteristic marker (positive in ~90–95%). Anti-thyroglobulin is less sensitive. A TSH-receptor blocking antibody may contribute.
• Histology (classic exam image/description):
  1. Dense lymphocytic infiltrate with germinal centres.
  2. Hürthle (Askanazy) cells — large oxyphilic follicular cells with abundant granular eosinophilic cytoplasm (packed with mitochondria).
  3. Follicular atrophy and fibrosis.

High-yield: Hürthle cell change + lymphoid germinal centres + anti-TPO positivity = Hashimoto thyroiditis. It is the commonest cause of goitrous hypothyroidism in iodine-sufficient areas and a risk factor for primary thyroid lymphoma (a rapidly enlarging goitre in a Hashimoto patient must raise this suspicion) and papillary carcinoma.

Clinically it often presents as a firm, painless, bosselated goitre. Patients may be euthyroid, hypothyroid, or transiently hyperthyroid (hashitoxicosis).

Pathophysiology

Thyroid hormone deficiency reduces basal metabolic rate and slows nearly every organ system. Accumulation of glycosaminoglycans (hyaluronic acid) in the dermis and other tissues draws in water → non-pitting myxoedema. Reduced cardiac output, bradycardia, decreased thermogenesis, slowed gut transit, and impaired free-water clearance (→ hyponatraemia) follow. Loss of negative feedback in primary disease drives TSH up, causing thyroid hypertrophy/goitre.

Clinical Features

Insidious and multisystem. Mnemonic for symptoms — think "everything slows down".

System	Features
General	Fatigue, cold intolerance, weight gain (modest), hypothermia
Skin/hair	Dry coarse skin, non-pitting myxoedema, periorbital puffiness, loss of outer third of eyebrows (madarosis/Queen Anne sign), brittle hair, carotenaemia (yellow palms)
Neuro	Slow speech, lethargy, poor memory, delayed relaxation of ankle jerk (hung-up reflex), carpal tunnel syndrome
Cardiac	Bradycardia, low-voltage ECG, pericardial effusion, diastolic hypertension, dyslipidaemia
GI	Constipation, ascites
Reproductive	Menorrhagia, oligomenorrhoea, infertility, hyperprolactinaemia (raised TRH)
Haem	Anaemia (normocytic; macrocytic if associated B12 deficiency)
Voice	Hoarse, husky (myxoedematous vocal cords)

High-yield: The delayed (hung-up) ankle reflex and periorbital puffiness with loss of lateral eyebrow are classic signature signs of hypothyroidism in exams.

Diagnosis & Investigation of Choice

Stepwise approach:

Suspect hypothyroidism → measure serum TSH (first-line screen) → if TSH high, measure free T4 → confirm primary hypothyroidism → check anti-TPO for aetiology.

Interpretation table:

TSH	Free T4	Diagnosis
High	Low	Overt primary hypothyroidism
High	Normal	Subclinical hypothyroidism
Low/normal	Low	Central (secondary) hypothyroidism
Low	High	Thyrotoxicosis (not hypothyroidism)

High-yield: In central hypothyroidism, never rely on TSH to titrate therapy — TSH is low/inappropriately normal. Monitor and target free T4 instead. Also, always exclude/treat co-existing adrenal insufficiency before starting thyroxine in pituitary disease, to avoid precipitating an adrenal crisis.

Other findings: hyponatraemia, raised CK, raised LDL/total cholesterol, raised prolactin, macrocytosis, low-voltage ECG/sinus bradycardia. Ultrasound shows a heterogeneous, hypoechoic gland in Hashimoto. Radionuclide uptake scan is not routinely needed.

Management / Drug of Choice

Levothyroxine (L-T4) is the drug of choice — it is the synthetic prohormone deiodinated peripherally to active T3, giving a smooth, stable T3 level (half-life ~7 days).

• Full replacement dose: ~1.6 µg/kg/day in healthy adults; titrate to normal TSH.
• Young, healthy: can start at/near full dose.
• Elderly or known/suspected ischaemic heart disease: start LOW (12.5–25 µg/day) and go slow — abrupt full replacement can precipitate angina/MI or arrhythmia.
• Administration: on an empty stomach, 30–60 min before breakfast, with water. Separate from calcium, iron, PPIs, and bile-acid sequestrants (these impair absorption).
• Monitoring: recheck TSH after 6 weeks (steady state) and adjust; once stable, annually.

High-yield: Target TSH in primary hypothyroidism is roughly 0.5–2.5 mIU/L (normal range; some aim mid-normal). In pregnancy, levothyroxine requirement rises by ~30–50% — increase the dose early (often empirically by ~2 extra tablets/week once pregnancy confirmed) and target a trimester-specific TSH (1st trimester <2.5 mIU/L).

Combination T4+T3 or desiccated thyroid extract is generally not recommended (unstable T3 levels).

Subclinical Hypothyroidism (raised TSH, normal free T4)

Treat (levothyroxine) when:

• TSH ≥ 10 mIU/L, OR
• TSH 4.5–10 with symptoms, positive anti-TPO, goitre, pregnancy/planning pregnancy, or dyslipidaemia/CV risk.

Otherwise observe and repeat TSH in 6–12 weeks (a single raised TSH may be transient).

High-yield: A pregnant or trying-to-conceive woman with subclinical hypothyroidism (especially anti-TPO positive) should be treated — untreated maternal hypothyroidism risks miscarriage, pre-eclampsia, and impaired fetal neurodevelopment.

Myxoedema Coma — the Emergency

Decompensated, life-threatening hypothyroidism. Usually an elderly woman in winter with longstanding/undertreated disease and a precipitant.

Precipitants: infection (commonest), cold exposure, MI/stroke, surgery/trauma, sedatives/opioids/anaesthetics, GI bleed, stopping thyroxine.

Features: altered mentation (lethargy → coma), hypothermia, hyponatraemia, hypoglycaemia, hypoventilation (hypercapnic respiratory failure), bradycardia/hypotension, non-pitting oedema.

Management flow: ICU/ABC → IV levothyroxine loading (with/without IV T3) → IV hydrocortisone (cover possible coadrenal insufficiency, give before/with thyroid hormone) → treat precipitant (broad-spectrum antibiotics) → passive rewarming, careful fluids/glucose, correct hyponatraemia slowly, ventilatory support.

• IV levothyroxine ~200–400 µg loading then daily; T3 may be added in severe cases.
• IV hydrocortisone 100 mg q8h — give before thyroid hormone if adrenal status unknown.
• Passive rewarming (active rewarming causes vasodilatation, shock).

High-yield: In myxoedema coma always give steroids (hydrocortisone) before/with thyroid hormone, treat infection, and rewarm passively. Mortality remains high (20–40%).

Congenital Hypothyroidism (CH)

The commonest preventable cause of intellectual disability — hence universal newborn screening.

• Cause: thyroid dysgenesis (agenesis/ectopic/hypoplastic) most common; dyshormonogenesis next (autosomal recessive, goitrous; Pendred = + deafness).
• Why screen: the neonate is often asymptomatic at birth (maternal T4 crosses placenta). Untreated → cretinism: coarse facies, macroglossia, umbilical hernia, hypotonia, prolonged jaundice, large posterior fontanelle, hoarse cry, constipation, lethargy, developmental delay.
• Screening: heel-prick capillary blood, measure TSH (± T4) at 48–72 h of life (avoid the physiological neonatal TSH surge of the first 24–48 h). Confirm with venous TSH/free T4.
• Treatment: start levothyroxine 10–15 µg/kg/day as early as possible (ideally within first 2 weeks) — early therapy preserves IQ.

High-yield: Newborn CH screening uses TSH on a heel-prick sample after 48 hours. Treatment is high-dose levothyroxine started urgently — every week of delay costs IQ points.

Complications

• Myxoedema coma (above).
• Cardiovascular: dyslipidaemia, accelerated atherosclerosis, pericardial effusion, diastolic hypertension.
• Reproductive: infertility, miscarriage, menorrhagia; in pregnancy — impaired fetal neurodevelopment.
• Neurological/psychiatric: depression ("myxoedema madness"), cerebellar ataxia, peripheral neuropathy, carpal tunnel.
• Growth: in children — growth failure, delayed bone age, delayed puberty (or Van Wyk–Grumbach syndrome = precocious puberty + large multicystic ovaries in severe juvenile hypothyroidism).
• Goitre/lymphoma in Hashimoto.

Key Differentials

Condition	Distinguishing feature
Euthyroid sick (non-thyroidal illness)	Low T3 (± low T4), TSH usually normal/low; in critically ill patient — do NOT treat, recheck after recovery
Subacute (de Quervain) thyroiditis	Painful tender goitre, raised ESR, post-viral, low RAIU; transient hypothyroid phase
Nephrotic syndrome	Oedema + low albumin; thyroid binding globulin lost in urine
Depression / chronic fatigue	Normal thyroid function tests
Down/Turner syndrome	Increased baseline risk of autoimmune hypothyroidism — screen

High-yield: In a critically ill ICU patient with low T3/T4 and normal TSH, suspect euthyroid sick syndrome — do not start levothyroxine; the abnormality reflects illness, not primary thyroid failure.

Recently asked / exam angle

• Image-based Hashimoto histology: Hürthle cells + lymphoid germinal centres → diagnosis and the antibody (anti-TPO).
• Interpreting TFT panels: distinguishing primary vs central vs subclinical from a TSH/free T4 grid — a recurring single-best-answer pattern.
• Levothyroxine dosing pearls: empty-stomach administration, ~1.6 µg/kg/day, start low in elderly/cardiac, pregnancy dose increase ~30–50%.
• Myxoedema coma management: the "steroids before/with thyroxine + passive rewarming + treat sepsis" sequence and IV T4 loading dose.
• Congenital hypothyroidism: screening test (TSH on heel-prick at 48–72 h) and the urgency of treatment; cretinism features (macroglossia, umbilical hernia, prolonged jaundice).
• Subclinical hypothyroidism treatment threshold: TSH ≥10, or lower with antibodies/pregnancy/symptoms.
• Pendred syndrome (dyshormonogenesis + deafness) and Wolff–Chaikoff effect (iodine-induced) as one-liner facts.
• Drug causes: amiodarone and lithium as MCQ stems.

Rapid revision

1. TSH is the single best screening test; high TSH + low free T4 = primary hypothyroidism.
2. Commonest cause worldwide = iodine deficiency; in iodine-replete areas = Hashimoto thyroiditis.
3. Hashimoto: anti-TPO antibody, lymphocytic infiltrate with germinal centres, Hürthle (Askanazy) cells, HLA-DR3/DR5.
4. Central hypothyroidism: low/normal TSH with low free T4 — titrate therapy to free T4, not TSH, and exclude adrenal insufficiency first.
5. Drug of choice = levothyroxine ~1.6 µg/kg/day, empty stomach, recheck TSH at 6 weeks.
6. Elderly/cardiac patients: start 12.5–25 µg and go slow to avoid precipitating angina/MI.
7. Pregnancy: levothyroxine needs rise ~30–50%; target 1st-trimester TSH <2.5 mIU/L.
8. Treat subclinical hypothyroidism if TSH ≥10, or if symptomatic/anti-TPO+/pregnant.
9. Myxoedema coma: IV T4 + IV hydrocortisone (give first), treat infection, passive rewarming; precipitant often infection/cold.
10. Classic signs: delayed (hung-up) ankle reflex, periorbital puffiness, loss of lateral eyebrow, hoarse voice, hyponatraemia, raised CK and cholesterol.
11. Congenital hypothyroidism: screen with TSH on heel-prick at 48–72 h; treat urgently with high-dose levothyroxine; dysgenesis is commonest cause.
12. Euthyroid sick syndrome (low T3, normal TSH in ICU) — do not treat; Pendred = dyshormonogenesis + deafness; Van Wyk–Grumbach = precocious puberty in severe juvenile hypothyroidism.