E7

• Thyroid hormone synthesis


  1. TSH binds to TSHR on basolateral membrane

  2. Iodide uptake by NIS

  3. Iodination of Tg tyrosyl residues by TPO (thyroperoxidase)

  4. Coupling of iodotyrosyl residues by TPO

  5. Export of mature Tg to colloid where it is stored
• T3


  Triiodothyronine, biologically active hormone
• T4


  Thyroxine, most abundant
• Deiodinase enzymes


  • D1, D2, D3 present in peripheral tissues
• Tests of thyroid function


  • Serum TSH
  • Serum free T4
  • Serum free T3
• Hyperthyroidism


  Low serum TSH, High serum free T4, High serum free T3
• Hypothyroidism


  High serum TSH, Low serum free T4, Low serum free T3
• Prevalence of thyroid disease


  • Hyperthyroidism: Prevalence 2.7%, Incidence 0.1%/year (more common in women)
  • Hypothyroidism: Prevalence 1.9%, Incidence 0.4%/year (more common in women)
  • Goitre: Prevalence 24.4%, Incidence 0.2% (more common in women)
• Aetiology of hyperthyroidism

  • Graves' hyperthyroidism
  • Toxic nodular goitre (single or multinodular)
  • Thyroiditis (silent, subacute): inflammation
  • Exogenous iodine
  • Factitious (taking excess thyroid hormone)
  • TSH secreting pituitary adenoma
  • Neonatal hyperthyroidism
• Symptoms and signs of hyperthyroidism


  • Cardiovascular: Tachycardia, Atrial fibrillation, Shortness of breath, Ankle swelling
  • Gastrointestinal: Weight loss, Diarrhoea, Increased appetite
  • Neurological: Tremor, Myopathy- muscle weakness, Anxiety
  • Eyes/skin: Sore, gritty eyes, Double vision, Staring eyes, Pruritus-itching
• Graves' disease


  60-80% of hyperthyroidism cases, Most prevalent autoimmune disorder in UK and US, Pathogenetic antibodies to TSH receptor on thyroid follicular cells (Long-Acting Thyroid Stimulators)
• Extrathyroidal manifestations of Graves' disease


  • Eyes: Lid lag/retraction, Conjunctival oedema (swelling), Periorbital puffiness (around eye), Proptosis (bulging), Ophthalmoplegia (weakness of eye muscles)
  • Skin: Pretibial myxoedema, Acropachy
• Neonatal hyperthyroidism


  TSH-R antibodies cross the placenta, Control hyperthyroidism in mother during pregnancy
• Diagnosis of hyperthyroidism


  • Clinical features of Graves', Iodine uptake scan: GD vs thyroiditis, Isotope imaging: GD vs TN hyperthyroidism, TPO Abs +ve in 75% of Graves', TSH receptor Abs +ve in 99% of Graves'
• Treatment of hyperthyroidism

  • Antithyroid drugs to block hormone synthesis, Surgical removal of thyroid, Radioiodine (131I) therapy
• Antithyroid drugs: thionamides


  Carbimazole (methimazole), Propylthiouracil - Block iodine incorporation and organification through inhibition of thyroperoxidase
• Thionamide therapy


  • Rapid control, well tolerated, Side effects: Rash, joint pains, sickness, Agranulocytosis, Liver disease with propylthiouracil, Pancreatitis with carbimazole, Low cure rate: 30-40% (lower in men)
• Surgery for hyperthyroidism

  Used infrequently, Pre-treatment with antithyroid drugs, Indications: Large goitre, Pregnancy, Pronounced ophthalmopathy, Patient preference
• Iodine-131


  Capsule (fixed dose), Highly effective (85% cure), Usually pre-treatment with drugs, May worsen eye disease (steroids)
• Risks of Iodine-131


  • Hypothyroidism (~60%), Cancer, Infertility, Teratogenesis (contra-indicated in pregnancy and breastfeeding)
• Treatment aims and prognosis


  To relieve symptoms, To restore T4 and T3 values within normal range, To obtain long-term normal thyroid function, 30% of patients with Graves' disease have normal thyroid function long-term following drugs, 131-I and surgery associated with > 50% risk of long-term hypothyroidism
• Aetiology of hypothyroidism


  • Autoimmune – Hashimoto thyroiditis, After treatment for hyperthyroidism, Subacute/silent thyroiditis, Iodine deficiency, Congenital (thyroid agenesis/enzyme defects)
• Hashimoto thyroiditis


  Inflammation and goitre/swelling of thyroid gland, Fibrosis and shrinkage
• Iodine deficiency


  Major cause of goitre and hypothyroidism world-wide, WHO identified in 7% of world's population, Supplementation programme
• Symptoms and signs of hypothyroidism

  • Cardiovascular: Bradycardia, Heart failure, Pericardial effusion, Gastrointestinal: Weight gain, Constipation, Skin: Myxoedema, Rash on legs, Vitiligo, Neurological: Depression, Psychosis, Carpal tunnel syndrome
• Levothyroxine


  Most common endocrine condition, Goal of therapy is to restore patients to euthyroid state and to normalise serum T4 and TSH concentrations
• Epidemiology of thyroid nodules


  • Discovered on palpation, imaging, incidentally, Very common in women, Increased in areas of low iodine intake, CT & MRI: 16%, Carotid doppler: 9.4%, PET scan 2-3%
• Significance of thyroid nodules


  May cause thyroid dysfunction, May cause compression, Need to exclude thyroid cancer, Prevalence of malignancy is 4 – 6.5%, Independent of nodule size, Malignancy risk in incidentalomas remains controversial, Risk of PET-positive thyroid nodule: 27%
• Prevalence of thyroid nodules


  • Nodules in 50-67% on high resolution ultrasound, Autopsy: 50% of population, Lifetime risk for developing palpable thyroid nodule in US: 10%, Increasingly found incidentally in patients undergoing imaging (CT, MRI, carotid doppler)
• Features suggestive of malignancy in thyroid nodules


  • Age less than 20 or more than 60, Firmness of nodule on palpation, Rapid growth, Fixation to adjacent structures, Vocal cord paralysis, Regional lymphadenopathy, History of neck irradiation, Family history of thyroid cancer
• Thyroid cancer is rare, less than 10% of nodules selected for surgery- important to select those with thyroid cancer
• Investigation of thyroid nodules

  • Assessment of thyroid function: Serum TSH, Serum free T4, Serum free T3, Thyroid antibodies, Assessment of thyroid size: Symptoms, X-ray thoracic inlet, CT or MRI of neck, Respiratory flow loop, Assessment of thyroid pathology: Radionuclide scanning, Ultrasound scanning, Fine needle aspiration cytology
• Thyroid ultrasound features

  • Benign nodule: Spongiform/honeycomb, Purely cystic, Eggshell calcification, Iso/hyper echoic (hypoechoic halo), Peripheral vascularity, Malignant nodule: Solid and hypoechoic, Irregular margin, Intramodular vascularity, Absence of halo, Taller than wide, Microcalcifications, Follicular lesion: Hyperechoic/homogeneous/halo benign, Hypoechogenicity/loss of halo suspicious
• Pathology of thyroid cancer

  • Papillary carcinoma (72-85%)- differentiated cancers (from follicular cells), Follicular carcinoma (10-20%)- differentiated cancers (from follicular cells), Anaplastic carcinoma (<1%), Medullary carcinoma (1.7-3%- from parafollicular C--cells)
• Aetiology of thyroid cancer


  • External irradiation, Iodine deficiency, Oncogene expression, Genetic factors (medullary Ca – MEN)
• Treatment of differentiated thyroid cancer

  • External beam DXT, Chemo Rx, Tyrosine kinase inhibitor Rx