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Thyroid disease

Thyroid disease. Prof Julian Davis Dept of Endocrinology Manchester Royal Infirmary. Thyroid gland. Soft gland, lower neck, anterior to trachea, below thyroid cartilage of larynx Makes thyroxine & T3 2 lobes + isthmus. Thyroid histology. Follicles Filled with colloid

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Thyroid disease

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  1. Thyroid disease Prof Julian Davis Dept of Endocrinology Manchester Royal Infirmary

  2. Thyroid gland • Soft gland, lower neck, anterior to trachea, below thyroid cartilage of larynx • Makes thyroxine & T3 • 2 lobes + isthmus

  3. Thyroid histology • Follicles • Filled with colloid • Lined with columnar epithelium: thyroid follicular cells • make thyroglobulin • Interspersed C-cells • Make calcitonin

  4. Thyroid hormone synthesis • Thyroid hormones are thyronines: tyrosine derivatives with iodine • Tetraiodothyronine = T4 • Triiodothyronine = T3 • Thyronines made from thyroglobulin…

  5. Thyroid hormone synthesis NIS • TFCs make thyroglobulin (Tg) under control of TSH, activated by TSHR, and secrete it into “colloid” • Iodide is trapped by TFCs (sodium-iodide symporter, NIS) and transported into colloid • Tg provides source of tyrosines • Thyroid peroxidase (TPO) on luminal membrane of TFCs iodinates tyrosines • ‘organification of iodine’) TSHR I Tg Tg TPO I Tg in colloid Iodide in colloid

  6. Organification of iodine by TPO

  7. Organification of iodine by TPO

  8. Organification of iodine by TPO

  9. Thyroid hormone synthesis – last stage! T3 NIS • TFCs endocytose Tg from luminal border • Endosomes/lysosomes: • hydrolysis of Tg, release of T4 into blood • Transport in blood bound to binding proteins • Thyroid-binding globulin etc • Deiodination T4  T3: active intracellular hormone • T3R is a nuclear hormone receptor, DNA binding, transcriptional effects TSHR T4 Tg Tg TPO Tg in colloid

  10. Pituitary-thyroid hormone axis Negative feedback of T4/T3 on pituitary TSH and hypothalamic TRH Low T4  increased TSH High T4  suppressed TSH

  11. Thyroid function tests Total T4: includes TBG-bound T4: 50-150nmol/L Free T4: only free hormone: 10-25pmol/L Total T3 Free T3 TSH Antibodies: TPO Abs TSH-R Abs Overactive thyroid: high T4 and T3 low TSH Underactive thyroid: low T4 high TSH Beware… - pregnancy raises TBG - OCP raises TBG - funny tests: - antibodies - drugs: amiodarone - pituitary disease - wrong patient

  12. Management of thyroid disorders • Thyrotoxicosis • Features, tests • Thyroid eye disease • risks • treatment options: • beta-blockers • antithyroid drugs • radioiodine • near-total thyroidectomy • Hypothyroidism • Features, tests • Treatment; T4 & T3 • Goitre & nodules

  13. Causes of thyrotoxicosis • Graves’ disease • Antibody stimulation of TSH-receptor • ‘Molecular mimicry’ • Autoimmune mechanism, may remit • Multinodular goitre • Autonomous multiple thyroid nodules • Uncertain pathogenesis, won’t remit • Solitary toxic nodule • Solitary benign adenoma • ?TSH receptor activating mutation • Drugs • Interferon • amiodarone

  14. Thyrotoxicosis • Common • 2% in women, 0.2% in men • Graves’ disease – autoimmune: possible remission • Multinodular goitre • Solitary nodule • Cardiovascular effects • higher pulse and BP, heart function • Atrial Fibrillation: 3x risk in >60s

  15. Thyrotoxicosis Weight loss + good appetite Tachycardia = palpitations; AF Sweating, heat intolerance Irritability, mood swings Frequent bowel action ?goitre Eye signs: lid retraction Thyroid eye disease: exophthalmos (proptosis) chemosis, peri-orbital oedema Tests (eg): fT4 raised 77pmol/L (10-22) TT3 raised 7.9nmol/L (1.1-3.0) TSH suppressed <0.01mU/L (0.2-3.0)

  16. Thyroid eye disease Risks: intraocular pressure: optic nerve damage exposure, corneal ulceration Treatment: steroids, immunosuppression surgical decompression, radiotherapy

  17. Cardiovascular mortality • Conclusion: • Use TSH as tissue marker • Consider treating low TSH • Requires prospective trial • to evaluate intervention Parle et al, 2001

  18. Treatment options for thyrotoxicosis • Beta-adrenergic blockers • Antithyroid drugs • carbimazole (methimazole) • propylthiouracil • Radioactive iodine • Surgery • sub-total, near-total thyroidectomy

  19. Antithyroid drugs • Carbimazole (methimazole in Europe and USA) • single daily doses OK • Propylthiouracil (PTU) • shorter half-life, thrice daily doses (150mg  40mg CBZ) Most UK patients receive these initially, for 6-24 months Remission after stopping: 50-60% at 1y 40% at 10y - no reliable markers for predicting remission (large goitre, severe toxicosis, high TSAb  worse risk)

  20. Drug regimens Titration Block-replace Initial CBZ dose 40mg 40mg subsequent dose 5-10mg decrements continue 40mg T4 - 100g when T4 normal; then adjust Duration 18-24 months 6 months Pregnancy OK No!

  21. Problems of ATDs • Side-effects • rash, itching (3-5%) • nausea, vomiting • mild leucopenia • agranulocytosis • 0.1-0.5% risk of significant infection • screening not normally done in UK • written warning leaflets advised • hospitalisation, antibiotics

  22. Radioactive iodine 131I: - and - emitter - first used 1946; 1948 in NW region - now 700 / year in Manchester - capsule or liquid format • Problems & precautions • Cancer risk

  23. Radioiodine - in practice • Dose • detailed dosimetry not helpful • low hypothyroid rates = high failure rates • ATD pretreatment • sometimes used to prevent thyroid crisis • should stop 5-7d before dose

  24. Radioiodine - hypothyroidism

  25. Radioiodine - cancer risk? Follow-up registers: 7417 patients treated 1950-1991 634 cancer diagnoses observed - 761 expected 448 cancer deaths - 499 expected Conclusion No overall excess risk Vigilance needed - younger age groups now treated

  26. Radioiodine – does it cause infertility? No!

  27. 131I - practical advice & doses <400MBq 400-600 600-800 NO close contact (<1m) with children & pregnant mums 9 days 12 days 14days Only <15 minutes contact 21 days 25 days 27days No adult in same bed - 4 days 8days Public transport (<1h) OK not OK not OK  1st dose = 400MBq; repeat doses = 550-799MBq; pregnancy tests routine

  28. Radioiodine and eye disease • Eye disease may worsen after radioiodine, but... • often transient • especially smokers • may relate to T-cell activation after RAI • reduced by prednisolone • Best treatment of Graves with TED is still ATDs, but leaves risk of relapse; good case now to use RAI with steroids; • Radioiodine can be used with care in selected patients

  29. Radioiodine summary • Safe • Hypothyroidism inevitable • No apparent cancer risk • No fertility problems • …but no pregnancy for 6 months after • Restrictions on contact up to 3 weeks • Care with eye disease

  30. Thyroidectomy • Near-total thyroidectomy • remnant tissue <2g • patient takes T4 post-op • relapse rate <2% • Complication rates • operator-dependent, experience-dependent (prefer >20 cases/year) • should be low for 1st operation: • vocal cord paralysis <1% • permanent parathyroid damage 2-4% • bleeding <2% • keloid scars

  31. Thyroid surgery - summary Choose your surgeon Explain risks RLN parathyroids bleeding keloid scar Hypothyroidism inevitable

  32. Case: thyrotoxicosis • 40-year old woman • First episode of thyroid disease • Moderate soft diffuse goitre • No eye disease • Free T4 34pmol/L • T3 5.2nmol/L • TSH <0.01mU/L • 2 children, age 10y, 8y

  33. Hypothyroidism Causes: autoimmune: Hashimoto’s destructive therapy Features, tests TSH & ‘subclinical’ disease Replacement therapy T4, T3

  34. Hashimoto’s thyroiditis = chronic lymphocytic thyroiditis, “1st” autoimmune disease T-cell infiltration, destruction of thyroid tissue  hypothyroidism Autoantibodies to TPO, Tg Women > men, 10:1, age 40s +

  35. Hypothyroidism (myxoedema) – features Weight gain Lethargy ++ Cold intolerance Cool dry skin Dry brittle hair, nail changes Constipation, heavy periods Muscle cramps Tests: T4 low TSH raised T3 unhelpful – often maintained low-normal

  36. Prevalence of subclinical hypothyroidism Whickham survey: 2779 adults, 1972-74 20y follow-up 1995: 1877 survivors, 96% followed up

  37. TSH as a critical test TSH >2mU/L increases risk of developing hypothyroidism in next 20y Positive TPO Abs increases risk further TSH >2 is within lab ranges, but the range is skewed, and lab reference populations include people predisposed to future thyroid failure TSH >2 indicates disturbance of HPT axis: implication for T4 replacement therapy Vanderpump, Clin Endocrinol, 1995

  38. Hypothyroidism - treatment Thyroxine (T4) 50-150g, mostly 100-125 g per day Once daily dose No side effects Monitor dose with TFTs

  39. Thyroid replacement - T3? Thyroid hormone production rates: T4 100g/day T3 30g/day - 80% from T4T3 conversion - 20% from thyroidal production Not all tissues equally able to convert T4 to T3 Most patients treated with T4 alone Long-standing unproven claims for T3 supplements

  40. Should we use T4 and T3? • Some benefits claimed from 1999 trial, but… • 12 Randomised controlled trials: no clear benefit • T3 dosing - would prefer slow release • Risks of transient over-replacement, NB risks of suppressed TSH, worries about predisposing to AF etc.

  41. Case: hypothyroid and tired • 32y woman • Diagnosed hypothyroid in 1998 • On T4 150g • freeT4 18pmol/L • TSH 1.33mU/L • c/o severe tiredness… • “is there a case for T3”? • Addison’s disease? • anaemia? • other associated diagnosis?

  42. Goitre = enlarged thyroid • Must assess thyroid status (toxic, hypo, euthyroid?) • Are there compression symptoms? Diffuse Graves’ disease Hypothyroidism (Hashimoto’s) Colloid goitre (euthyroid) Iodine deficiency; drugs (lithium etc) Multinodular

  43. Thyroid nodules – solitary lumps • Thyroid nodules common, increase with age • 30-60% of normal thyroids have nodules at autopsy; • may be part of multinodular disease • Palpation: 5-20% (>1cm) • U/S scan: 15-50% (>2mm) • Thyroid cancer rare: estimated <0.1% in USA

  44. Clinical signs – what matters Age, duration, iodine status, radiation exposure Thyroid status Presence of solitary nodule v. goitre, ?multinodular disease Pressure symptoms Mobility, skin tethering Lymph nodes RLN palsy

  45. Evaluation of thyroid nodules Frequent benign disease, low risk of malignancy Which nodules to evaluate? Solitary nodules >1cm in euthyroid patients ( risk in children, history of radiation, malignant features) Remain vigilant! Ultrasound Fine needle aspiration

  46. Diagnostic approach - FNA Unsatisfactory inadequate cellularity: 5-20% Benign ~70%: usually colloid nodules Suspicious 10-20%:“follicular neoplasm”... could be adenoma or carcinoma Malignant 5%, papillary, follicular, medullary carcinoma; lymphoma, metastasis

  47. Summary Thyrotoxicosis diagnosis & TFTs features treatment – ATDs, surgery, radioiodine Hypothyroidism diagnosis, role of TSH assays features treatment – T4 (T3) Goitre types (diffuse, MNG) Nodule evaluation (US, FNA)

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