Thyrotoxicosis and Hypothyroidism

Hyperthyroidism

Definitions, pathophysiology and classification

Hyperthyroidism denotes increased thyroid hormone synthesis and secretion; it is a subset of thyrotoxicosis, which describes the clinical-biochemical state of excess circulating thyroid hormone irrespective of source. This distinction is exam-critical: Graves disease, toxic multinodular goitre and toxic adenoma are hyperthyroid states; exogenous thyroxine excess and destructive release syndromes are thyrotoxic but not truly hyperthyroid.

Mechanistic class	Typical causes	Key discriminator
TSH receptor stimulation	Graves disease; gestational transient thyrotoxicosis; trophoblastic disease	Diffuse uptake; TRAb positive in Graves
Autonomous thyroid hormone synthesis	Toxic multinodular goitre; toxic adenoma; iodine-induced hyperthyroidism	Nodular uptake; older age; low/negative TRAb
Central hyperthyroidism	TSH-secreting pituitary adenoma; thyroid hormone resistance	High FT4/FT3 with non-suppressed TSH
Exogenous or ectopic hormone	Factitious thyroxine; struma ovarii; metastatic functioning thyroid carcinoma	Low uptake; thyroglobulin low in factitious ingestion

Graves disease is mediated by thyroid-stimulating immunoglobulins activating the TSH receptor, increasing iodide uptake, thyroglobulin iodination and hormone release. The normal adult reference ranges are assay-dependent, but typical values are TSH 0.4–4.0 mU/L, free T4 10–22 pmol/L and free T3 3.5–6.5 pmol/L. Overt hyperthyroidism shows suppressed TSH, usually <0.01 mU/L, with elevated FT4 and/or FT3; isolated T3-toxicosis is common in early Graves and toxic nodular disease.

Clinical assessment and risk stratification

Symptoms reflect adrenergic sensitisation and tissue hypermetabolism: weight loss with appetite, heat intolerance, tremor, palpitations, proximal myopathy, diarrhoea, oligomenorrhoea and neuropsychiatric disturbance. Signs include tachycardia, atrial fibrillation, warm moist skin, lid lag, brisk reflexes and goitre. Graves-specific features are orbitopathy, thyroid dermopathy and acropachy. In older patients, “apathetic thyrotoxicosis” may present predominantly with weight loss, depression, heart failure or atrial fibrillation.

Subclinical hyperthyroidism is suppressed TSH with normal FT4 and FT3. It is graded as TSH 0.1–0.39 mU/L or TSH <0.1 mU/L; treatment is generally favoured when TSH <0.1 mU/L in patients aged >65 years, or with atrial fibrillation, osteoporosis, cardiac disease or symptoms, consistent with European Thyroid Association guidance.

Investigation

First-line testing is serum TSH followed by FT4 and FT3 if TSH is low. TSH receptor antibodies are highly useful for Graves disease; modern binding or bioassay methods have sensitivity and specificity commonly >95% in untreated overt Graves disease. Thyroid peroxidase antibodies support autoimmunity but are not diagnostic of Graves. If the cause is unclear, radioiodine uptake or technetium-99m pertechnetate scintigraphy distinguishes diffuse, focal, multinodular and low-uptake patterns. Ultrasound is not required routinely, but assesses nodules, goitre anatomy and vascularity; Graves typically shows diffusely increased colour-flow Doppler vascularity.

Treatment

Initial symptomatic control is with beta-blockade. Propranolol 20–40 mg orally three or four times daily reduces tremor and tachycardia and, at higher doses, modestly inhibits peripheral T4-to-T3 conversion; alternatives include atenolol 25–50 mg daily or metoprolol 25–50 mg twice daily. Use diltiazem cautiously if beta-blockers are contraindicated.

Therapy	Typical adult regimen	Important examination points
Carbimazole	Initial 10–40 mg once daily according to severity; maintenance commonly 5–15 mg daily	Prodrug of methimazole; inhibits thyroid peroxidase-mediated organification and coupling; preferred outside early pregnancy
Propylthiouracil	100–150 mg three times daily initially; maintenance 50–150 mg daily in divided doses	Also inhibits type 1 deiodinase; preferred in first trimester and thyroid storm; greater severe hepatotoxicity risk
Radioiodine iodine-131	Fixed activity often 400–600 MBq, or dosimetry-based	Contraindicated in pregnancy and breastfeeding; hypothyroidism common; avoid or steroid-cover active Graves orbitopathy
Total/near-total thyroidectomy	Definitive surgical management after euthyroid preparation	Indications include large compressive goitre, suspicious nodules, patient preference, relapse, or contraindication to radioiodine

Antithyroid drugs may be used as dose titration or block-and-replace. Titration uses the lowest dose maintaining normal FT4/FT3; TSH may remain suppressed for months and should not guide early dose adjustment. Block-and-replace typically uses carbimazole 40 mg daily plus levothyroxine 100 micrograms daily once biochemically controlled, but is contraindicated in pregnancy. Standard treatment duration for Graves disease is 12–18 months; remission is more likely with small goitre, mild disease, female sex and falling/negative TRAb. Relapse rates after a course of antithyroid drug therapy are approximately 40–60%, compared with high definitive cure rates after radioiodine or surgery but at the cost of permanent hypothyroidism.

Serious antithyroid adverse effects are uncommon but high-yield. Agranulocytosis occurs in about 0.1–0.5%, usually within the first 3 months; patients must stop the drug and obtain urgent full blood count for fever or sore throat. Hepatotoxicity, cholestasis, rash, arthralgia and ANCA-associated vasculitis may occur. Routine serial white cell monitoring is not generally recommended; baseline FBC and liver function tests are prudent.

Thyroid storm

Thyroid storm is a life-threatening decompensation with fever, marked tachycardia, heart failure, delirium, gastrointestinal-hepatic dysfunction and precipitant such as infection, surgery or iodine load. The Burch-Wartofsky score supports diagnosis: scores ≥45 are highly suggestive, 25–44 indicate impending storm. Management is simultaneous: resuscitation and precipitant treatment; propranolol 60–80 mg orally every 4–6 hours or intravenous esmolol in ICU; PTU 500–1000 mg loading then 250 mg every 4 hours; iodine solution at least 1 hour after thionamide; hydrocortisone 100 mg intravenously every 6–8 hours; cooling and supportive care.

Hypothyroidism

Definitions, classification and pathophysiology

Hypothyroidism is failure of thyroid hormone action at tissue level, usually from deficient thyroxine secretion. In examinations, classification is crucial because TSH interpretation depends on an intact hypothalamic–pituitary axis. Reference intervals vary, but typical adult values are TSH 0.4–4.0 mU/L, free T4 10–22 pmol/L and free T3 3.5–6.5 pmol/L.

Category	Biochemistry	Common causes	Key exam point
Primary overt hypothyroidism	High TSH, low free T4	Autoimmune thyroiditis, post-radioiodine, thyroidectomy, iodine deficiency/excess, drugs	TSH is the most sensitive screening test in ambulatory patients
Subclinical hypothyroidism	High TSH, normal free T4	Early autoimmune disease, recovery phase after illness, drugs	Treatment depends on TSH threshold, age, symptoms, antibodies and pregnancy status
Central hypothyroidism	Low or inappropriately normal TSH, low free T4	Pituitary macroadenoma, surgery/radiotherapy, Sheehan syndrome, hypophysitis, infiltrative disease	Monitor treatment using free T4, not TSH
Peripheral thyroid hormone resistance/action defects	Variable	Rare receptor/transporter/deiodinase defects	Usually not an MRCP Part 1 therapeutic focus

Thyroid hormone deficiency reduces basal metabolic rate, myocardial contractility, heart rate, ventilatory drive and renal free-water clearance. Accumulation of glycosaminoglycans causes non-pitting myxoedema, delayed reflex relaxation and, in severe disease, serous effusions. Hyperprolactinaemia may occur through increased TRH stimulation, causing galactorrhoea or menstrual disturbance.

Aetiology and diagnostic evaluation

In iodine-replete countries, autoimmune hypothyroidism is the leading cause. Anti-thyroid peroxidase antibodies are present in approximately 90% of Hashimoto-type autoimmune hypothyroidism and predict progression from subclinical to overt disease. Annual progression is roughly 2–4% with raised TSH alone and up to 4–8% when anti-TPO antibodies are positive, higher when TSH exceeds 10 mU/L.

• Drug causes: amiodarone, lithium, interferon-α, immune checkpoint inhibitors, tyrosine kinase inhibitors, thionamides and iodine-containing contrast. Amiodarone contains about 37% iodine by weight and has a terminal half-life often exceeding 50 days.
• Biochemical associations: hyponatraemia, hypercholesterolaemia, raised creatine kinase, macrocytosis, normocytic anaemia and hyperprolactinaemia.
• Central disease clues: headaches, visual field defects, hypogonadism, adrenal insufficiency, diabetes insipidus or previous cranial irradiation. Always assess cortisol reserve before replacing thyroxine if hypopituitarism is possible.

Non-thyroidal illness may show low T3, low/normal T4 and low/normal TSH; routine testing during acute illness is discouraged unless thyroid disease is strongly suspected. A mildly raised TSH should generally be repeated after 6–12 weeks before diagnosing persistent subclinical hypothyroidism.

Clinical severity and myxoedema coma

Severe decompensated hypothyroidism is rare but high-mortality, classically precipitated by infection, cold exposure, sedatives, myocardial infarction or poor adherence. Despite the term, coma is not mandatory. Features include hypothermia, bradycardia, hypotension, hypoventilation, hypoglycaemia, hyponatraemia, ileus and altered consciousness. The Popoveniuc diagnostic score assigns points for thermoregulatory, CNS, cardiovascular, gastrointestinal and metabolic disturbances; scores ≥60 support myxoedema coma, 25–59 suggest risk, and <25 make it unlikely.

Treatment: levothyroxine and special situations

Levothyroxine is synthetic T4, highly protein-bound, converted peripherally to T3, with a half-life of approximately 7 days in euthyroid subjects. It should be taken fasting with water, ideally 30–60 minutes before breakfast, separated by at least 4 hours from calcium, iron, bile-acid sequestrants or sucralfate. Proton pump inhibitors, coeliac disease, Helicobacter pylori gastritis, bariatric surgery and poor adherence are common reasons for persistently raised TSH.

Clinical setting	Initial levothyroxine strategy	Monitoring target
Young/fit adult with overt primary hypothyroidism	Approximately 1.6 micrograms/kg/day, commonly 75–125 micrograms daily	TSH in reference range; recheck every 6–8 weeks after dose change
Elderly or ischaemic heart disease	Start 12.5–25 micrograms daily; increase by 12.5–25 micrograms every 4–6 weeks	Avoid angina, arrhythmia and overtreatment
Central hypothyroidism	Replace cortisol first if ACTH deficiency possible; then levothyroxine	Free T4 in upper half of reference range; TSH unreliable
Pregnancy or planning pregnancy	Increase established dose by about 25–30% once pregnancy confirmed	Trimester-specific TSH; often target <2.5 mU/L in first trimester
Myxoedema coma	IV levothyroxine 200–400 micrograms loading, then 50–100 micrograms IV daily; hydrocortisone 100 mg IV 8-hourly until adrenal insufficiency excluded	ICU supportive care; cautious T3 only in selected cases

Combination T4/T3 therapy is not routine. Randomised trials have not shown consistent symptomatic or cognitive benefit over levothyroxine monotherapy, and excess T3 risks atrial fibrillation and bone loss. Current British Thyroid Association and American Thyroid Association guidance supports levothyroxine monotherapy for most patients.

Subclinical hypothyroidism: thresholds and evidence

Treatment is generally recommended when TSH is persistently >10 mU/L, particularly with positive anti-TPO antibodies, goitre, symptoms, dyslipidaemia or pregnancy intent. For TSH 4–10 mU/L, decisions are individualised. The TRUST trial in adults aged ≥65 years with persistent subclinical hypothyroidism showed levothyroxine improved TSH but did not improve hypothyroid symptom scores or tiredness at 1 year, supporting conservative management in many older asymptomatic patients.

Over-replacement is common and clinically important: suppressed TSH, especially <0.1 mU/L, increases atrial fibrillation risk and accelerates bone loss, particularly in postmenopausal women. Dose requirements fall with ageing and weight loss, and rise with pregnancy, oestrogen therapy, nephrotic syndrome and enzyme-inducing drugs such as carbamazepine, phenytoin and rifampicin.

Thyroiditis

Thyroiditis denotes inflammatory thyroid disorders causing follicular injury, altered hormone release, and variable recovery or permanent failure. For MRCP, the key distinction is between destructive thyroiditis, where preformed T4/T3 leak from damaged follicles and radioactive iodine uptake is low, and hormone overproduction as in Graves’ disease, where uptake is high. This distinction determines management: antithyroid drugs have no physiological role in destructive thyroiditis.

Classification and pathophysiology

Entity	Mechanism	Typical clinical context	Radioiodine uptake	Outcome
Subacute granulomatous thyroiditis de Quervain	Post-viral immune-mediated follicular destruction; granulomas with multinucleate giant cells	Painful tender thyroid, fever, malaise; often after URTI; raised ESR/CRP	Low, usually <5% at 24 h	Usually complete recovery; permanent hypothyroidism in ~5–15%
Painless/silent thyroiditis	Autoimmune lymphocytic destructive thyroiditis; anti-TPO often positive	Painless small goitre; thyrotoxic symptoms without ophthalmopathy	Low	Recurs; permanent hypothyroidism in ~10–20%
Postpartum thyroiditis	Immune rebound after pregnancy in TPO-antibody-positive women	Within 12 months postpartum, classically 2–6 months	Low, but radionuclide scanning usually avoided in breastfeeding unless necessary	Permanent hypothyroidism in ~20–50% over 5–10 years
Hashimoto thyroiditis	Chronic autoimmune thyroiditis: T-cell-mediated cytotoxicity and anti-TPO/anti-thyroglobulin antibodies	Firm painless goitre or atrophic gland; hypothyroidism; transient “hashitoxicosis” possible	Variable; low during destructive phase	Progressive hypothyroidism common
Drug-induced thyroiditis	Direct cytotoxicity or immune activation	Amiodarone type 2, interferon-α, IL-2, lithium, checkpoint inhibitors	Low in destructive forms	Variable; may require steroids or long-term levothyroxine
Acute suppurative thyroiditis	Bacterial infection, often via pyriform sinus fistula or immunosuppression	Severe focal pain, fever, erythema, dysphagia; usually euthyroid	Not central diagnostically	Requires antibiotics/drainage; rare but serious
Riedel thyroiditis	Fibrosing thyroiditis, often IgG4-related; invasive fibrosis	Hard “woody” fixed thyroid, compressive symptoms; mimics malignancy	Variable	May need glucocorticoids, tamoxifen, decompression

Triphasic clinical course

Destructive thyroiditis classically follows a triphasic pattern: a thyrotoxic phase lasting approximately 2–8 weeks, a hypothyroid phase lasting 2–6 months, then recovery. Biochemistry shows suppressed TSH, elevated FT4/FT3 during the initial phase; however, FT3 elevation is often proportionately less than in Graves’ disease because hormone release is passive rather than T3-biased synthesis. Normal adult reference ranges vary, but typical values are TSH 0.4–4.0 mU/L, FT4 10–22 pmol/L, and FT3 3.5–6.5 pmol/L.

Diagnostic approach

Examination should identify thyroid pain, nodularity, fever, eye signs, dermopathy, bruits, and compressive features. In subacute thyroiditis, ESR is commonly >50 mm/h and CRP elevated; leukocytosis may occur. TSH receptor antibodies support Graves’ disease; modern third-generation TRAb assays have sensitivity and specificity generally >95% for Graves’ disease in appropriate clinical contexts. Anti-TPO antibodies occur in Hashimoto, painless, and postpartum thyroiditis but are not diagnostic alone.

• Low uptake scan: destructive thyroiditis, factitious thyrotoxicosis, iodine-induced states.
• High diffuse uptake: Graves’ disease.
• Patchy/nodular uptake: toxic multinodular goitre or toxic adenoma.
• Ultrasound Doppler: reduced vascularity in destructive thyroiditis; markedly increased flow in Graves’ disease (“thyroid inferno”).

Radioiodine imaging is contraindicated in pregnancy and generally avoided during breastfeeding unless feeding is interrupted according to isotope-specific guidance. In postpartum thyroiditis, the diagnosis is usually clinical and serological.

Management

Problem	Treatment	Key exam points
Adrenergic symptoms in thyrotoxic phase	Propranolol 10–40 mg orally 6–8 hourly, or modified-release 80–160 mg daily	Use cautiously in asthma, decompensated heart failure, heart block; atenolol may be used once daily but avoid/limit in pregnancy depending on context.
Painful subacute thyroiditis	NSAID, e.g. ibuprofen 400–600 mg three times daily	First-line if mild/moderate pain.
Severe pain or systemic symptoms	Prednisolone 20–40 mg daily, taper over 2–6 weeks	Rapid pain response within 24–48 h is typical; relapse can occur if taper too rapid.
Hypothyroid phase	Levothyroxine, commonly 50–100 micrograms daily; lower starting dose in elderly/IHD	Treat if symptomatic, TSH persistently >10 mU/L, pregnancy/planning pregnancy, or significant goitre. Reassess withdrawal after 6–12 months if transient thyroiditis suspected.
Suppurative thyroiditis	Urgent broad-spectrum IV antibiotics, culture-directed therapy, abscess drainage	Consider CT neck and ENT review; exclude pyriform sinus fistula, particularly with recurrent left-sided disease.

Carbimazole, methimazole, and propylthiouracil are ineffective in destructive thyroiditis because new hormone synthesis is not the driver of thyrotoxicosis. This is a common examination discriminator. Exceptions arise when thyroiditis coexists with Graves’ disease or amiodarone-induced thyrotoxicosis type 1.

Postpartum and drug-induced thyroiditis

Postpartum thyroiditis affects approximately 5–10% of women overall, rising to 30–50% in TPO-antibody-positive women and higher in type 1 diabetes. It may present as isolated thyrotoxicosis, isolated hypothyroidism, or a biphasic illness. Thyroid function should be checked at 3 and 6 months postpartum in high-risk women, and annually thereafter if TPO-positive or after an episode. During pregnancy or when trying to conceive, levothyroxine is generally indicated if TSH is >4.0 mU/L, and often at lower thresholds in TPO-positive patients depending on local guidance.

Amiodarone-induced thyroiditis is examined frequently. Amiodarone contains approximately 37% iodine by weight, has a very long terminal half-life of about 40–60 days, and causes either type 1 iodine-induced hormone synthesis in abnormal glands or type 2 destructive thyroiditis. Type 2 disease typically has low uptake, low/normal vascularity, and is treated with prednisolone 30–40 mg daily tapered over 2–3 months; mixed forms may require combined glucocorticoid and thionamide therapy under specialist care.

Follow-up and complications

Monitor TSH and FT4 every 4–6 weeks during evolution until stable, then less frequently. Persistent hypothyroidism beyond 6–12 months, high anti-TPO titres, female sex, and recurrent disease predict permanent failure. Red flags requiring urgent evaluation include marked unilateral swelling, sepsis, stridor, vocal cord palsy, hard fixed goitre, cervical lymphadenopathy, or failure of presumed subacute thyroiditis to improve with appropriate anti-inflammatory treatment, as malignancy, abscess, or Riedel thyroiditis may mimic benign inflammatory disease.