12.4 Thyrotoxicosis, Thyroiditis & Management of Hyperthyroidism

Thyroid disorders encompass a wide spectrum of functional, autoimmune, and neoplastic pathologies frequently encountered in MRCP(UK) Part 1. Candidates must master the laboratory differentiation of primary, secondary, and subclinical thyroid dysfunction, the aetiological distinction between autonomous hyperfunctioning glands and destructive thyroiditis, evidence-based management across pregnancy and thyroid storm, and the histopathological classification of thyroid malignancies.

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1. Hyperthyroidism & Thyrotoxicosis: Aetiology & Investigation

Thyrotoxicosis vs. Hyperthyroidism

• Thyrotoxicosis: The clinical, physiological, and biochemical syndrome resulting from excess circulating free thyroid hormones (free T4 and/or free T3), regardless of the underlying source.
• Hyperthyroidism: Specifically denotes sustained de novo overproduction and hypersecretion of thyroid hormones by a hyperfunctioning thyroid gland.

Primary Aetiologies of Thyrotoxicosis

Aetiological Breakdown of Thyrotoxicosis:
- Graves' Disease (~75%): TSH-receptor autoantibodies (TRAb) → Diffuse toxic hyperplasia + Extrathyroidal signs
- Toxic Multinodular Goitre (Plummer's, ~15%): Autonomous functional nodules → Patchy isotope uptake, older patients
- Toxic Solitary Adenoma (~5%): Single somatic mutation (TSHR/Gs-alpha) → Unifocal "hot" nodule with suppressed remainder
- Destructive Thyroiditis (~5%): Release of stored preformed hormone → Very low / suppressed isotope uptake (<1%)
- Exogenous / Factitious: Ingestion of levothyroxine → Low uptake, undetectable serum thyroglobulin

Graves' Disease: Pathognomonic Features

• Immunopathogenesis: Caused by circulating immunoglobulin G (IgG) autoantibodies directed against the TSH receptor (TRAb / TSI) on thyroid follicular cells. TRAb binds and constitutively activates the receptor, stimulating cyclic AMP cascades that drive uninhibited thyroid hormone synthesis and diffuse follicular hyperplasia.
• Extrathyroidal Manifestations (Specific to Graves'):
  1. Graves' Orbitopathy (Thyroid Eye Disease): Orbital fibroblasts express TSH receptors and IGF-1 receptors. Activation by TRAb triggers T-cell infiltration and synthesis of hydrophilic glycosaminoglycans (hyaluronic acid) by orbital fibroblasts, causing adipogenesis and extraocular muscle oedema (inferior and medial recti most commonly affected). Signs: exophthalmos, chemosis, periorbital fullness, lid retraction (Dalrymple's sign), lid lag (von Graefe's sign), diplopia, and optic nerve compression. Active smoking multiplies the risk and severity by 5- to 8-fold.
  2. Pretibial Myxoedema (Thyroid Dermopathy): Infiltration of glycosaminoglycans into the dermis of the anterolateral lower leg, producing non-pitting, violaceous, indurated plaques with an "orange-peel" (peau d'orange) texture. Almost exclusively seen in patients with severe orbitopathy and very high TRAb titres.
  3. Thyroid Acropachy: Extreme manifestation characterized by digital clubbing, soft-tissue swelling of hands/feet, and periosteal new bone formation.
  4. Thyroid Bruit: Auscultation of a continuous vascular murmur over the thyroid gland reflects intense hypervascularity and high-volume blood flow.
• Diagnostic Confirmation: Positive serum TRAb (>95% sensitivity and specificity); high-affinity 99mTc-pertechnetate or 123-I isotope scan demonstrates homogenous, diffuse, intensely elevated radiotracer uptake.

Toxic Multinodular Goitre (TMNG) & Toxic Solitary Adenoma

• TMNG (Plummer's Disease): Commonest cause of thyrotoxicosis in elderly individuals or areas of borderline iodine deficiency. Arises from somatic activating mutations in the TSH receptor gene within multiple discrete nodules. Characteristically lacks orbitopathy or pretibial myxoedema. Isotope scanning shows heterogeneous, patchy distribution with multiple hot and cold areas.
• Toxic Solitary Adenoma: Single autonomous adenoma harboring a clonal activating mutation in TSHR or GNAS genes. Isotope scan reveals a solitary "hot" nodule with complete suppression of radiotracer uptake in the remainder of the normal thyroid parenchyma.

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2. Thyroiditis: Comparative Differential Diagnosis

Destructive thyroiditis causes transient thyrotoxicosis through inflammatory necrosis of follicular cells, releasing preformed stored colloid into the systemic circulation. It typically follows a triphasic clinical course: Transient Thyrotoxic Phase (2–6 weeks) → Transient Hypothyroid Phase (2–8 weeks) → Euthyroid Recovery (>90%).

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3. Management of Hyperthyroidism & Thyroid Storm

Pharmacotherapy: Thionamides

• Carbimazole: First-line antithyroid drug in the UK (prodrug converted rapidly to active methimazole). Inhibits thyroid peroxidase (TPO), blocking iodination of tyrosine residues and coupling of iodotyrosines:
  • Titration Regimen: Start carbimazole 20–40 mg daily, titrating downwards every 4–6 weeks as free T4/T3 normalize, maintaining a euthyroid state for 12–18 months before trial of cessation (remission rate ~50%).
  • Block-and-Replace Regimen: Carbimazole 40 mg daily combined with levothyroxine 100 mcg daily once euthyroidism is achieved, continued for 12–18 months. Block-and-replace is strictly contraindicated in pregnancy.
• Propylthiouracil (PTU): Inhibits TPO and also blocks peripheral 5'-deiodinase (inhibiting conversion of T4 to T3):
  • Indications: (1) First trimester of pregnancy (weeks 1–12): Carbimazole carries teratogenic risks of embryopathy, aplasia cutis congenita, and choanal atresia; PTU is preferred in early pregnancy, switching back to carbimazole in the second trimester to avoid maternal hepatotoxicity. (2) Thyroid storm. (3) Carbimazole intolerance/allergy.
  • Black Box Warning: Rare risk of severe, fulminant drug-induced hepatic necrosis.
• Agranulocytosis: Most feared complication of thionamides ($0.2\text{–}0.5%$ of patients; absolute neutrophil count $< 0.5 \times 10^9/\text{L}$). Idiosyncratic; peaks within the first 3 months. Mandatory Patient Safety Advice: All patients must be explicitly counselled to stop the drug immediately and obtain an urgent full blood count (FBC) at the nearest emergency department if they develop a sore throat, mouth ulcers, unexplained fever, or systemic infection. Never initiate empirical antibiotics or wait for outpatient review without verifying the neutrophil count.

Radioiodine Therapy (131-I) & Surgery

• Radioiodine-131: Emits beta particles destroying follicular tissue. First-line definitive therapy for toxic multinodular goitre, toxic solitary adenoma, and relapsed Graves'.
  • Absolute Contraindications: Pregnancy, breastfeeding, planned pregnancy within 6 months, and active moderate-to-severe Graves' orbitopathy (radioiodine releases thyroid autoantigens, worsening eye disease; if 131-I is used in mild orbitopathy, concurrent oral prednisolone prophylaxis is mandatory).
• Total / Subtotal Thyroidectomy: Indicated for large compressive goitres, coexisting suspicious malignant nodules, patient refusal/contraindication to radioiodine, or severe Graves' orbitopathy. Complications: transient or permanent hypoparathyroidism (hypocalcaemia), recurrent laryngeal nerve palsy (hoarseness / bilateral airway compromise), haematoma.

Thyroid Storm (Accelerated Thyrotoxic Crisis)

Life-threatening hypermetabolic emergency with mortality up to 20–30%. Precipitated by infection, trauma, surgery, DKA, or radioiodine. Diagnosed clinically via the Burch-Wartofsky Point Scale (evaluating hyperpyrexia, agitation/coma, tachycardia/AF, congestive heart failure, and GI-hepatic dysfunction):

Thyroid Storm 5-Pillar Emergency Protocol:
1. Beta-Blockade: IV Propranolol (1–2 mg IV slow push) or Esmolol → Controls adrenergic surge and blocks peripheral T4→T3 conversion
2. Antithyroid Drug: PTU (500–1000 mg loading, then 250 mg q4h PO/NG) → Inhibits de novo synthesis and peripheral conversion (superior to carbimazole)
3. Inorganic Iodine: Lugol's Iodine (or potassium iodide) given AT LEAST 1 HOUR AFTER PTU → Wolff-Chaikoff effect blocks release (giving iodine before PTU accelerates hormone synthesis!)
4. Corticosteroids: IV Hydrocortisone (100 mg q6h) → Treats relative adrenal insufficiency and inhibits peripheral T4→T3 conversion
5. Supportive / Cooling: External cooling blankets, paracetamol (avoid aspirin: displaces T4 from thyroid-binding globulin)

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