6.3 Thyroid Disorders: Hypothyroidism, Thyrotoxicosis & Thyroid Storm
Key Takeaways
Interpretation of thyroid function tests (TFTs) distinguishes primary hypothyroidism (elevated TSH, low FT4) and subclinical hypothyroidism (elevated TSH, normal FT4) from thyrotoxicosis (suppressed TSH < 0.05 mU/L, elevated FT4/FT3).
Under NICE NG145, levothyroxine for primary hypothyroidism starts at about 1.6 micrograms/kg/day in adults under 65 without cardiovascular disease, but at 25–50 mcg daily in those aged 65 or over or with cardiovascular disease, to avoid precipitating angina or arrhythmias.
Graves' disease is characterized by TSH receptor stimulating antibodies (TSHR-Ab), thyroid eye disease, and pretibial myxoedema; first-line medical therapy is carbimazole (propylthiouracil in the first trimester of pregnancy), and patients must be warned to immediately stop the drug and obtain an urgent full blood count if they develop fever, sore throat, or mouth ulcers due to life-threatening agranulocytosis.
Thyroid storm (thyrotoxic crisis) is a life-threatening medical emergency presenting with hyperpyrexia, severe tachycardia or atrial fibrillation, delirium, and heart failure; immediate multimodal therapy comprises beta-blockers (propranolol), high-dose antithyroid drugs (propylthiouracil), Lugol's iodine (administered at least 1 hour after the antithyroid drug), and IV hydrocortisone.
Thyroid Disorders: Hypothyroidism, Thyrotoxicosis & Thyroid Storm
In accordance with NICE guideline NG145 (Thyroid disease: assessment and management) and British Thyroid Association standards, thyroid disorders are among the most common endocrine conditions encountered in UK clinical practice. The hypothalamic-pituitary-thyroid (HPT) axis regulates metabolic homeostasis via thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3). Accurate diagnosis requires structured interpretation of thyroid function tests (TFTs) combined with targeted clinical assessment.
Thyroid Function Test (TFT) Interpretation Framework
| Biochemical TFT Pattern | Serum TSH | Serum Free T4 (FT4) | Serum Free T3 (FT3) | Primary Clinical Diagnoses & Next Steps |
|---|---|---|---|---|
| Primary Hypothyroidism | Elevated (> 4.5 mU/L) | Low (< 12 pmol/L) | Normal or Low | Autoimmune Hashimoto's thyroiditis (anti-TPO positive), post-ablative, iodine deficiency. Initiate levothyroxine |
| Subclinical Hypothyroidism | Elevated (typically 5–10 mU/L) | Normal (12–22 pmol/L) | Normal | Early thyroid failure. Consider treatment if TSH ≥ 10 mU/L on 2 occasions; consider a 6-month trial if under 65 with symptoms and TSH raised but below 10 (NICE NG145) |
| Secondary (Central) Hypothyroidism | Low or Inappropriately Normal | Low (< 12 pmol/L) | Low | Pituitary adenoma, hypopituitarism. Must evaluate adrenal axis before starting levothyroxine! |
| Primary Hyperthyroidism (Thyrotoxicosis) | Suppressed (< 0.05 mU/L) | Elevated (> 22 pmol/L) | Elevated | Graves' disease (TSHR-Ab+), Toxic multinodular goitre, Toxic adenoma. Proceed to etiology workup |
| T3 Toxicosis | Suppressed (< 0.05 mU/L) | Normal | Elevated | Early Graves' disease or autonomous toxic adenoma; predominantly T3 secretion |
| Subclinical Hyperthyroidism | Suppressed (< 0.05 mU/L) | Normal | Normal | Exogenous levothyroxine excess or mild autonomous nodular disease. Increases risk of atrial fibrillation and osteoporosis |
| Non-Thyroidal Illness (Sick Euthyroid) | Normal or Low | Normal or Low | Low | Critical non-thyroidal systemic illness; altered peripheral deiodination. Do not give thyroid hormone |
Caution
Central Hypothyroidism Pitfall: When a low FT4 is accompanied by a normal or low TSH, suspect pituitary disease. Never initiate levothyroxine without first testing for and treating co-existing secondary adrenal insufficiency. Administering levothyroxine accelerates hepatic cortisol metabolism and can precipitate a fatal acute Addisonian crisis if cortisol deficiency is uncorrected.
Hypothyroidism
Aetiology & Clinical Features
Primary hypothyroidism in the UK is most commonly caused by Hashimoto's thyroiditis (chronic autoimmune thyroiditis characterized by lymphocytic infiltration, thyroid follicle destruction, and high titres of anti-thyroid peroxidase [anti-TPO] and anti-thyroglobulin [anti-Tg] antibodies). Other causes include atrophic thyroiditis, radioactive iodine therapy, thyroid surgery, severe iodine deficiency, and drug toxicity (amiodarone, lithium).
- Clinical manifestations: Weight gain, lethargy, cold intolerance, constipation, bradycardia, dry skin, coarse brittle hair, periorbital puffiness, non-pitting myxoedema, carpal tunnel syndrome, menorrhagia, and characteristic delayed relaxation phase of deep tendon reflexes ("hung-up" reflex).
Levothyroxine Replacement Therapy
Oral levothyroxine (synthetic T4) is the treatment of choice:
- Adults under 65 with no history of cardiovascular disease: Consider a starting dose of 1.6 micrograms/kg/day (rounded to the nearest 25 mcg; NICE NG145), taken on an empty stomach with water, 30–60 minutes before breakfast.
- Adults aged 65 or over, or with a history of cardiovascular disease: Start at 25–50 mcg once daily, titrating slowly according to TSH (rechecked every 3 months until stable). Rapid normalization of thyroid hormone levels abruptly increases myocardial oxygen consumption and cardiac output, risking acute myocardial ischaemia, angina, or fatal arrhythmias.
- Pregnancy: Thyroid hormone is vital for early fetal neurodevelopment. Women with pre-existing hypothyroidism must increase their levothyroxine dose by 25–50% as soon as pregnancy is confirmed, targeting serum TSH in the lower trimester-specific reference range.
- Subclinical Hypothyroidism Guidelines:
- TSH 10 mU/L or higher on 2 occasions 3 months apart: consider levothyroxine (NICE NG145), even without symptoms.
- TSH above the reference range but below 10 mU/L on 2 occasions 3 months apart: for adults under 65 with symptoms, consider a 6-month trial of levothyroxine, stopping if symptoms do not improve. Otherwise, monitor TFTs (anti-TPO positivity predicts progression and justifies closer monitoring). Seek specialist advice in pregnancy or when planning conception.
Hyperthyroidism & Thyrotoxicosis
Thyrotoxicosis describes the clinical syndrome of hypermetabolism resulting from elevated circulating thyroid hormones. Primary hyperthyroidism arises from excessive glandular synthesis.
Differentiation of Common Aetiologies
| Feature | Graves' Disease | Toxic Multinodular Goitre (Plummer's) | Subacute de Quervain's Thyroiditis |
|---|---|---|---|
| Underlying Mechanism | Autoimmune stimulation of TSH receptors by TSHR-stimulating antibodies (TRAB) | Autonomous hyperfunctioning thyroid follicular nodules | Post-viral granulomatous inflammation; follicular disruption and colloid release |
| Typical Demographics | Young to middle-aged females (20–50 years) | Older adults (> 50–60 years); long-standing goitre | Young/middle-aged adults following viral upper respiratory tract infection |
| Physical Examination | Smooth, diffuse, non-tender goitre with audible thyroid bruit | Irregular, multinodular, non-tender goitre without bruit | Exquisitely tender, painful enlarged thyroid; fever |
| Extrathyroidal Signs | Graves' orbitopathy (exophthalmos, chemosis, diplopia), pretibial myxoedema, thyroid acropachy | None (absence of autoimmune eye or skin signs) | None; systemic viral symptoms, malaise |
| Radioiodine Uptake Scan | Diffuse, homogeneous increased uptake throughout gland | Patchy, heterogeneous uptake with "hot" and "cold" areas | Markedly diminished / absent uptake (< 1%) |
| Inflammatory Markers | Normal ESR and CRP | Normal ESR and CRP | Markedly elevated ESR (> 50–100 mm/h) and CRP |
| Clinical Management | Carbimazole, radioiodine, or surgery; beta-blockers for symptoms | Radioiodine ablation or surgery; antithyroid drugs produce temporary remission | Symptomatic: NSAIDs (or prednisolone if severe) + beta-blocker. Antithyroid drugs are ineffective |
Management of Graves' Disease
- Symptomatic Relief: Propranolol (non-selective beta-blocker) provides rapid relief from adrenergic symptoms (tremor, palpitations, anxiety, heat intolerance) while awaiting antithyroid drug efficacy.
- Antithyroid Drugs (Thionamides):
- Carbimazole: First-line thionamide in the UK. Inhibits thyroid peroxidase (TPO), preventing iodination of tyrosine residues and coupling of iodotyrosines.
- Propylthiouracil (PTU): Second-line thionamide. Preferred during the first trimester of pregnancy due to carbimazole-induced embryopathy (aplasia cutis, choanal atresia), and preferred in thyroid storm because it additionally blocks peripheral 5'-deiodinase (preventing T4 to T3 conversion). Carries a black-box warning for severe hepatotoxicity.
- Radioiodine (131-I) Ablation: Highly effective definitive therapy. Absolute contraindications include pregnancy and breastfeeding. Critical caveat: Radioiodine exacerbates active moderate-to-severe Graves' ophthalmopathy due to release of TSH receptor antigens; mild eye disease requires prophylactic oral corticosteroid cover.
- Surgery (Total or Subtotal Thyroidectomy): Indicated for large compressive goitres, suspected malignancy, or patient refusal/contraindications to radioiodine. Complications include recurrent laryngeal nerve damage (vocal hoarseness) and accidental excision/ischaemia of the parathyroid glands causing acute hypocalcaemia (perioral numbness, carpopedal spasm, positive Chvostek's and Trousseau's signs).
Warning
Carbimazole & Agranulocytosis: Carbimazole causes idiosyncratic bone marrow suppression resulting in agranulocytosis (neutrophils < 0.5 × 10^9/L) in 0.2–0.5% of patients. Every patient commenced on carbimazole or PTU must receive written and verbal safety counselling: If you develop a sore throat, mouth ulcers, or unexplained fever, STOP the medication immediately and seek an urgent same-day full blood count (FBC). Never prescribe empirical antibiotics without checking the neutrophil count.
Thyroid Storm (Thyrotoxic Crisis)
Thyroid storm is an acute, life-threatening exacerbation of thyrotoxicosis carrying a mortality of 10–30%. It is usually precipitated by infection, trauma, surgery (thyroid or non-thyroid), diabetic ketoacidosis, childbirth, or abrupt cessation of antithyroid drugs in patients with untreated or inadequately controlled hyperthyroidism.
Clinical Presentation
- Hyperpyrexia: Extreme fever typically > 38.5°C to 41.0°C, out of proportion to any apparent infection, accompanied by profuse diaphoresis.
- Cardiovascular collapse: Severe tachycardia (often > 140 bpm), atrial fibrillation, high-output congestive cardiac failure, hypotension, and circulatory shock.
- Central nervous system dysfunction: Agitation, delirium, extreme restlessness, psychosis, confusion, seizures, or coma.
- Gastrointestinal / Hepatic dysfunction: Nausea, persistent vomiting, diarrhoea, severe abdominal pain, and cholestatic jaundice (poor prognostic marker).
Multimodal Emergency Resuscitation Protocol
Management requires concurrent interventions targeting adrenergic overdrive, hormone synthesis, hormone release, and peripheral conversion:
Hypoparathyroidism & Post-Thyroidectomy Hypocalcaemia
Hypoparathyroidism most often follows thyroid or parathyroid surgery (damage to or removal of the parathyroid glands); autoimmune and congenital causes (22q11.2 deletion) are rarer. Low PTH causes hypocalcaemia with high phosphate.
- Features: perioral and fingertip paraesthesia, muscle cramps, carpopedal spasm (Trousseau's sign), facial twitching on tapping the facial nerve (Chvostek's sign), seizures and a prolonged QT interval.
- Severe or symptomatic hypocalcaemia: IV 10% calcium gluconate (for example 10–20 mL over 10 minutes, then an infusion) with cardiac monitoring; check and correct magnesium.
- Long-term: oral calcium and an active vitamin D analogue (alfacalcidol or calcitriol), aiming for low-normal calcium to avoid hypercalciuria.
Other thyroid surgery complications include recurrent laryngeal nerve injury (hoarseness) and a neck haematoma causing airway compression, which is an emergency needing the wound opened at the bedside.
A 34-year-old woman presents to the general practice surgery with a 1-week history of palpitations, anxiety, heat intolerance, and severe anterior neck pain that radiates to her ears and jaw. She reports having a flu-like upper respiratory illness three weeks ago. On examination, she is diaphoretic with a fine postural tremor. Her pulse is 108 bpm and regular. Palpation of her anterior neck reveals an enlarged, exquisitely tender thyroid gland. Laboratory tests show: TSH < 0.02 mU/L, free T4 of 32 pmol/L, and an erythrocyte sedimentation rate (ESR) of 88 mm/h. A diagnostic technetium-99m thyroid uptake scan demonstrates markedly diminished, near-absent tracer uptake (< 1%). What is the most appropriate management?
Initiate carbimazole 20 mg once daily
Prescribe oral ibuprofen and propranolol
Administer radioactive iodine-131 ablation
Urgent referral for total thyroidectomy
A 28-year-old woman with newly diagnosed Graves' disease was commenced on carbimazole 30 mg daily and propranolol three weeks ago. She presents to the emergency department with a 2-day history of high fever, rigors, and an excruciatingly painful sore throat with difficulty swallowing. On physical examination, her temperature is 38.9°C, heart rate is 112 bpm, and her pharynx is markedly erythematous with extensive aphthous-type ulcerations and tonsillar exudate. What is the most appropriate immediate clinical action?
Reduce the carbimazole dose to 15 mg daily and arrange routine outpatient bloods
Prescribe oral amoxicillin 500 mg three times daily and review in 48 hours
Stop carbimazole immediately and arrange an urgent full blood count to exclude agranulocytosis
Reassure the patient that viral pharyngitis is common and advise paracetamol
A 45-year-old woman with inadequately treated Graves' disease undergoes emergency laparoscopic appendicectomy for perforated appendicitis. In the post-anaesthesia care unit, she becomes acutely agitated, delirious, and profusely diaphoretic. Her temperature is 39.8°C, heart rate is 158 bpm in irregular atrial fibrillation, and her sclerae appear jaundiced. A diagnosis of thyroid storm is confirmed. Intravenous propranolol is administered, and propylthiouracil (PTU) 1000 mg is delivered via nasogastric tube. Lugol's iodine solution is prescribed. What is the fundamental physiological rationale for delaying the administration of Lugol's iodine until at least 1 hour after giving PTU?
To allow complete gastric emptying so that iodine absorption is not impaired by stomach contents
To prevent an immediate severe acute anaphylactoid reaction to concentrated elemental iodine
To ensure adequate renal excretion of PTU prior to the systemic absorption of iodine
To prevent the exogenous iodine from acting as an organification substrate for new thyroid hormone synthesis
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