Thyroid Disease. Sam Rowe, MBBS, MAEd, FRCPC Banff, Alberta November 25, 2011

Transcription

1 Thyroid Disease Sam Rowe, MBBS, MAEd, FRCPC Banff, Alberta November 25, 2011

2 Disclosure last 2 years: Lilly HypoCCS Study Investigator Bristol-Myers Squibb - Speaker GlaxoSmith Kline Advisory Board

3 OBJECTIVES At the conclusion of this presentation, participants will know the differential diagnosis and have a logical approach to the investigation of patients with: a) Signs and symptoms of hypothyroidism b) Signs and symptoms of hyperthyroidism c) Single or multiple thyroid nodules

4 Thyroid Develops from endodermal epithelium in the foregut Migrates from the base of the tongue to the neck

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6 Thyroid grams in size in adults; huge potential for growth

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8 Thyroid Isthmus over the second or third tracheal ring Right lobe often slightly larger than the left

9 T 3 triiodothyronine T 4 thyroxine half-life 0.75 days Relative potency 1.0 Only 20% of T 3 is secreted by the thyroid T 3 is 99.7% protein bound metabolism of T 3 is through deiodination 5 deiodination inactivates T 3 half-life 6.7 days Relative potency % secreted by the thyroid T 4 is 99.98% protein bound metabolism of T 4 is through deiodination 5 deiodination converts T 4 to inactive reverse T 3

10 Control of Secretion of T 3 and T 4 When T 3 and T 4 levels drop, hypothalamus releases TRH. TRH causes the pituitary to secrete TSH (and Prolactin) TSH, half-life 30 minutes, stimulates T 3, T 4 synthesis, thyroid enlargement TSH is inhibited by: - Dopamine/Dopamine agonists - Phenytoin - Somatostatin and analogues - High dose glucocorticoids TSH is stimulated by: - GLP-1 - alpha adrenergic agonists

11 TSH shares an alpha subunit with FSH, LH and hcg As a result - gestational hyperthyroidism - physiologic hyperthyroidism of pregnancy - trophoblastic tumors may cause hyperthyroidism TSH range mu/l; tends to rise with age

12 What can go wrong with thyroid function? Hyperthyroidism Hypothyroidism Development of thyroid enlargement, diffuse or nodular

13 Hyperthyroidism A 33 year old woman presents with fatigue, palpitations, tremor and weight loss. Most likely diagnoses: - Graves Disease (50-80%) - Toxic adenoma or toxic multinodular goitre - Thyroiditis silent, subacute Less likely: - Over replacement - Thyrotoxicosis factitia - Drug induced: lithium, interferon, amiodarone - Struma ovarii - Metastatic thyroid cancer

14 Features of Hyperthyroidism Palpitations Tachycardia Atrial fibrillation Congestive heart failure Increased calcium excretion Demineralization of bone Weight loss Proximal muscle weakness Heat intolerance Emotional lability Increased renal blood flow, GFR Increased RBC mass Nervousness Lid retraction Hair loss Soft, friable nails Menstrual inrregularities

15 Graves Disease Auto Immune Thyroid Disease May show antibodies against TPO, thyroglobulin and TSH receptor History tends to be chronic, > 3 months May be associated with other auto immune diseases pernicious anemia, DM Type I, ITP, vitiligo, myasthenia gravis, Addison s disease, RA, SLE Specific clinical findings orbitopathy, pretibial myxedema High radioiodine uptake Diffuse Goitre

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23 Toxic Nodular Thyroid Disease Palpable thyroid nodule(s) Nodular disease on ultrasound Focal increased uptake on nuclear medicine scan History tends to be chronic, >3 months Typical patients are > 50

24 Follicular adenoma

25 Hot Nodules

26 Treatment of Hyperthyroidism Graves Disease - anti thyroid drugs (PTU, methimazole), ß blockers - radioactive iodine - surgery P.T.U. now not used as first line in adults or children (rare cause of hepatic failure) Still used in the first trimester of pregnancy Also used in thyroid storm because of blockage of T4 T3 conversion Methimazole can be prescribed once a day, but is generally prescribed 20 to 30 mg per day initially, (10 mg bid or tid) Antithyroid drug therapy for months if no permanent remission, radioiodine Radioiodine need to wait until rendered euthyroid by antithyroid drugs Surgery not much used in North America

27 Treatment of Hyperthyroidism Thyroid adenoma or Multinodular goitre Surgery Radioactive iodine After radioactive iodine patients will probably not be hypothyroid

28 Treatment of Hyperthyroidism Thyroiditis ß blockade antithyroid drugs Steroids Pain relief NSAIDS Await spontaneous resolution May have transient/permanent hypothyrodism

29 Patients likely to relapse after Antithyroid Drug Therapy for Graves Disease 1. Previous cause of ATD therapy with recurrence 2. Long history of symptoms 3. Young, male 4. Family history of auto immune thyroid disease 5. Cigarette smoking 6. Presence of ophthalmopathy 7. Pronounced hyperthyroidism at the beginning of therapy 8. High ATD dose at the end of therapy 9. Pronounced TSHRAb titre 10. Large goitre 11. Increase in size of goitre 12. Nodular goitre, or high intrathyroid flow on Doppler Overall recurrence rate 50-60%

30 43 year old woman presents with fatigue, weight gain, constipation and cold intolerance. Most likely diagnosis: Hashimoto s Disease Rule out: - subacute/silent thyroiditis - Pituitary Disease? Duration of symptoms, Associated Pituitary Symptoms? Previous thyroid disease, Radioiodine therapy or surgery? TSH level? Drugs? Goitrogens? Pain

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32 Causes of Hypothyroidism Congenital Acquired iodine deficiency Hashimoto s disease Drugs (eg lithium, Iodine) Post surgery Goitrogens (cabbage, turnips, rutabaga) Thyroid infiltration (sarcoidosis, scleroderma) Central Pituitary Hypothalamic

33 Replacement Therapy for Hypothyroidism Normally 20% of T 3 is secreted directly from the gland; 80% is converted from T 4 Therefore in patients on T 4 replacement: Levels of T 4 are higher than normal if T 3 is maintained at the normal level Feedback inhibition of TSH relies on T 3 and T 4

34 T 3 Replacement Therapy T 3 is rapidly absorbed, with a peak at 2 to 4 hours Short half-life, 0.75 days (T days) Therefore fluctuations in biologic activity over the course of the day T 4 considered safer for long term regular replacement No advantage to T 3 /T 4 mixtures on meta analysis

35 Dessicated Thyroid Animal preparations contain higher ratios of T 3 :T 4 than the human thyroid May lead to supraphysiologic T 3 concentrations soon after administration Batch to batch variation Not recommended

36 Special Considerations in Thyroid Hormone Dosing Dose needs to be increased: 1. In pregnancy (especially the first trimester), dose 25-30% 2. Where absorption is interfered with by medications - iron (ferrous sulphate) - calcium (carbonate) - cholestyramine - sucralfate - aluminum hydroxide - espresso coffee

37 Special Considerations in Thyroid Hormone Dosing (cont d) Dose needs to be increased: 3. In GI Disorders - celiac disease - small bowel resection - bypass procedures - impaired gastric secretion (atrophic gastritis) 4. Where metabolism is increased by drugs (P450) - estrogen - phenytoin - carbamazepine - rifampin 5. Where there is interference with deiodination - cirrhosis - amiodarone therapy

38 Special Considerations in Thyroid Hormone Dosing (cont d) Dose needs to be decreased: In patients over 65, with decreased thyroid hormone clearance In women receiving androgen therapy for breast cancer

39 Thyroiditis Subacute, infectious Viral, bacterial Silent Post Partum (often confused with PP blues) Auto immune Hyperthyroidism self-limited, may be followed by hypothyroid phase Total duration 3 4 months

40 Other Agents Causing Thyroiditis Most cases are related to activation or exacerbation of auto-immune disease IL-2 Interferon - alpha GM CSF Can precipitate silent thyroiditis

41 Amiodarone-Induced Thyroiditis RAIU 4 hours <1% 62 year old man Hyperthyroid On Amiodarone therapy

42 56 year old woman presents with a palpable 2 cm right sided nodule.? Sudden onset associated with pain likely to be hemorrhage into a cyst Otherwise, majority of thyroid nodules are asymptomatic and only 5-10% are malignant.? Single or multiple nodules? Male vs Female? Young vs Old? Solid vs Cystic? Hot vs Cold? Mobile vs Fixed? Hoarseness, Dysphagia? Lymphadenopathy? History of radiation exposure

43 Evaluation of Thyroid Nodules Anatomical evaluation ultrasound, solid vs cystic Functional evaluation nuclear medicine hot vs cold Histological evaluation FNA if nodule > 1 cm Unless associated with other features suspicious for malignancy nodules < 1 cm should be re-examined in 6-12 months, to see if there has been interval change

44 Follicular neoplasm

45 Cold Nodule

46 FNAB of Papillary Thyroid Cancer

47 Lithium Therapy Lithium, like iodine, inhibits thyroid hormone release High doses inhibit organification Some patients develop a goitre (up to 40%) and hypothyroidism (20%) Some may develop silent thyroiditis, even Graves Disease Lithium may be used to make radioactive treatment more effective

48 Amiodarone and Thyroid Function Amiodarone has significant iodine content and some structural similarity to T 4 Inhibits deiodination of T 4 T 3 Therefore relatively increased T 4 concentrations to maintain normal T 3 May interfere with T 3 binding to receptors Iodine normally causes an initial inhibition of iodine processing and then an escape (Wolff-Chaikoff) In some patients on amiodarone: prolonged inhibition without escape leads to goitre formation and hypothyroidism Many of these patients have auto immune thyroid disease

49 Amiodarone and Hyperthyroidism In some patients, hyperthyroidism may develop Amiodarone-induced thyrotoxicosis Type I Jod-Basedow effect Development of Graves Disease in pre-disposed individuals (more common in Europe, iodine deficiency predisposes) Type II direct cytotoxic effect of iodine causing thyroiditis (more common in North America no iodine deficiency)

50 Used for Tyrosine Kinase Inhibitors (e.g. Sunitinib) Renal cell carcinoma Gastro intestinal stromal tumors Causes follicular cell apoptosis and thyroid destruction Thyroid function must be monitored in patients on Tyrosine Kinase Inhibitors Hence use of these agents to slow the progression of thyroid cancer

51 Use of Radioactive Iodine Treatment 1. For treatment of hyperthyroidism (Graves, nodular disease) - generally considered safe 2. For treatment of thyroid cancer - The risk of a secondary primary malignancy may be slightly increased - Risks may outweigh benefits when the cumulative dose rises above 37 GBq I (3)

52 Thyroid Cancer

53 Thyroid Disease Take Home Points 1. T 4 has long half life do not test too often. 2. Do not overreact to subtle changes in TSH 3. Check T 3, T 4 in conjunction with TSH 4. Increase dose L-thyroxine in pregnancy 5. Watch fetus carefully in patients who have had Graves Disease 6. Watch Iron, calcium supplements in patients on T 4 7. Do not use T 3 or dessicated thyroid for routine replacement 8. Patients on replacement T 4 following thyroid cancer removal need TSH completely suppressed

54 References 1. Nayak B, Hodak SP (2007) Hyperthyrodism, Endocrinol Metab Clinic N Am 36: Devdhar M, Ousman YH, Burman KD (2007) Hypothyrodism, Endocrinol Metab Clin N Am 36: Megedus L (2009) Treatment of Graves Hyperthyroidism: Evidence Based and Emerging Modalities. Endocrinol Metab Clin N Am 38: Benker G, Reinwein D, Kahaly G et al (1998) Is there a methimazole dose effect on remission rate in Graves disease? Results from a long-term perspective study. The European Multicentre Trial Group of the Treatment of Hyperthyroidism with Antithyroid Drugs. Clin Endocrinol (Oxf) 49 (4): Williams D (2008) Twenty years experience with post-chernobyl Thyroid Cancer. Best Practice and Research Clinical Endocrinology and Metabolism 22 (6): Sinnott B, Ron E, Schneider AB (2010) Exposing the Thyroid to Radiation: A Review of Its Current Extent, Risks, and Implications. Endocrine Reviews 31: Bogazzi F, Giovannetti C, Fossehatsion R et al (2010) Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal. J Clin Endocrinol Metab 95(1): Miller MC (2010) The Patient with a Thyroid Nodule. Med Clin N Am 94: Reid SM, Middleton P, Cossich MC, Crowther CA(2010) Interventions for clinical and subclinical hypothyroidism in pregnancy. Cochrane Database of Systematic Reviews, Issue 7 Art No: CD007752

55 References (continued) 10. Acharya, S.H., Avenell, A., Philip, S., Burr, J., Bevan, J.S. & Abraham, P. (2008) Radioiodine therapy (RAI) for Graves disease (GD) and the effect on ophthalmopathy: a systematic review. Clinical Endocrinology, 69: Duntas LM, Biondi B (2011) New Insights into Subclinical Hypothyroidism and Cardiovascular Risk. Seminars in Thrombosis and Hemostasis. 37 (1): Bomeli, SR, LeBeau SO, Ferris RL (2010). Evaluation of a thyroid nodule. Otolaryngol Clin N Am 43: Azizi F, Amouzegan A (2011) Management of hyperthyroidism during pregnancy and lactation. European Journal of Endocrinology 164: Mitchell AL, Pearie SHS (2010). How should we treat pateints with low serum thyrotropin concentrations? Clinical Endocrinology 72: Cox AE, LeBeau, SO (2011) Diagnosis and Treatment of Differentiated Thyroid Carcinoma. Radiol Clinc N AM 49: Fallahi, B, Adabi, K; Majidi, M Fard-Esfahani, A Heshmat, R Larijani, B Haghpanah, V. Incidence of Second Primary Malignancies During a Long-term Surveillance of Patients With Differentiated Thyroid Carcinoma in Relation to Radioiodine Treatment. Clinical Nuclear Medicine 36(4): Grozinsky-Glasberg, S; Fraser, A; Nabshoni, E; Weizman A: Leibovici L. Thyroxine-Triiodothyronine Combination Therapy Versus Thyroxine Monotherapy for Clinical Hypothyroidism: Meta-Analysis of Randomized Controlled Trials. JClin Endocrinol Metab 91: Lorenzo C, Haffner SM (2010) Performance Characteristics of the New Definition of Diabetes. Diabetes Care 33: