grave's hyperthyroidism

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  1. 1. Presented by Cam Roessner, PharmD Student An Impending Storm: Graves Disease Thyrotoxicosis May 5, 2015
  2. 2. Outline the etiology, pathophysiology, clinical presentation, and complications of hyperthyroidism/thyrotoxicosis Review alternatives for the treatment of thyrotoxicosis secondary to Graves disease Understand the evidence and rationale behind the common treatment modalities for Graves disease and be able to identify the medication- related needs of patients with Graves disease thyrotoxicosis Learning Objectives 2
  3. 3. Introduction to Patient Case Hyperthyroidism Background Goals of Therapy & Drug Therapy Problems DRP #1 Symptomatic management DRP #2 Graves treatment DRP #3 Thyroidectomy pre-treatment DRP #4 Thionamide adverse effects Case Resolution and Monitoring Summary References Presentation Outline 3
  4. 4. History of Presenting Illness 40 year old LL with a 3-4 month history of tremor, diaphoresis, heat intolerance, palpitation, 12 lb. unintentional weight loss, irregular menses, and insomnia Past Medical History Hyperthyroidism ( 1 month) Cesarean section ( 2) Social and Family History Ex-smoker (quit 1 year ago) 2 sisters with hypothyroidism Patient Case 4
  5. 5. Medications Propylthiouracil (PTU) 150mg PO tid Switched from MMI 6 days before admission Atenolol 50mg PO bid Increased from once daily 6 days before admission Past Medications Methimazole (MMI) 30mg PO daily No response after 1 month trial Patient developed bilateral rash, skin peeling and arthralgia of hands Patient Case 5
  6. 6. Patient Case System Relevant Labs, Vital Signs, and Physical Examination Findings CNS & Psych A & O 3, anxious mood, restless, insomnia HEENT lid lag/thyroid stare, enlarged thyroid with bruit CVS BP 144/75mmHg, HR 114, ECG sinus tachycardia, ECHO normal, JVP 1cm, palpitations Resp RR 20, 97% on room air, crackles, wheeze GI NVD, abdomen soft and non-tender, ALT = 51 Renal Scr 38umol/L, eGFR 128mL/min Endo free T4 > 100pmol/L (10.0 25.0pmol/L) free T3 > 50pmol/L (3.5 6.5pmol/L) TSH = 0.04mU/L (0.5 4.0mU/L) PTH = 4ng/L (7 37ng/L) Autoantibodies: TSH-receptor antibody (TRab) = 90IU/L (negative) Heme & Electrolytes Neut 1.2 10E9/L (2.0 9.0 10E9/L) Ca2+ = 2.77 (2.10 2.55mmol/L) MSK & Integument tremor, palmar erythema, proximal muscle weakness, hyperreflexia, arthralgia of hands Miscellaneous Temp 37.7C, heat intolerant 6
  7. 7. 7 Thyrotoxicosis secondary to Graves disease Patient Diagnosis
  8. 8. Differential Diagnosis of Thyrotoxicosis and an Overview of Graves disease 8
  9. 9. Hyperthyroidism Disorders that result from sustained overproduction and release of hormone by the thyroid itself Thyrotoxicosis Refers to the physiologic manifestations of excessive quantities of the thyroid hormones Not necessarily associated with the thyroid gland (i.e. thyroid hormone ingestion, known as thyrotoxicosis factitia) Definitions 9 Mandel, S. J., Larsen, P. R., & Davies, T. E. (2011)
  10. 10. Toxic adenoma Toxic multinodal goiter Thyroid carcinoma TSH-secreting pituitary adenoma Iodine-induced hyperthyroidism Drug-induced hyperthyroidism Graves Disease Thyrotoxicosis Differential Diagnosis 10 Robert James Graves 1796-1853 NEJM, 358(24), 2594-2605 Marino, M., Vitti, P., & Chiovato, L. (2010)
  11. 11. Composed of a T and B cell-mediated immune process Autoantibodies, TSH-receptor antibodies or Thyroid-stimulating antibodies (TRabs or TSabs) are capable of stimulating thyroid hormone production independent of natural TSH secretion Thyroid hypertrophy, increased vascularity, and unregulated thyroid hormone (T3 and T4) secretion result Graves is thought to be caused by a complex interplay of genetic, hormonal, and environmental factors (infection, stress, smoking, iodine) Graves disease Etiology and Pathophysiology 11 Marino, M., Vitti, P., & Chiovato, L. (2010)
  12. 12. 12 Thyroid Symmetrically enlarged thyroid with thrill or bruit Skin Warm, moist, with palmar erythema, friable hair, and soft nails Cardiovascular Tachycardia, palpitations, and arrhythmias (premature beats to atrial fibrillation) are common GI Increased appetite, increased liver enzymes, diarrhea Nervous System Insomnia, irritability, restlessness, decreased concentration, fine tremor, thyrotoxic stare/lid lag (autonomic hyperstimulation of the upper eyelid) Graves disease Clinical Presentation Marino, M., Vitti, P., & Chiovato, L. (2010)
  13. 13. 13 Thyrotoxic stare (left) and an enlarged non-nodular thyroid gland (right) are common findings in Graves disease, however they are non-specific and can occur in other thyrotoxic states. Thyrotoxic Stare & Enlarged Thyroid Gland Marino, M., Vitti, P., & Chiovato, L. (2010)
  14. 14. 14 Graves Ophthalmopathy
  15. 15. 15 Muscles Weakness and easy exhaustion Skeletal Increased bone remodeling and osteoporosis depending on the duration of disease and coexistence of other risk factors Heme Mild leukopenia (separate from effects of thionamides) Reproductive Oligomenorrhea or amenorrhea in women (severe thyrotoxicosis) and gynecomastia in men Metabolic Heat intolerance and weight loss Graves disease Clinical Presentation Marino, M., Vitti, P., & Chiovato, L. (2010)
  16. 16. 16 Autoantibodies TRab Positive Very sensitive and specific with 98% of untreated patients with Graves disease positive for TSH-receptor antibodies Confirms the diagnosis if there is uncertainty on presentation Lab Abnormalities TSH Undetectable or low Free T3 (FT3) Elevated Free T4 (FT4) Elevated Graves Disease Marino, M., Vitti, P., & Chiovato, L. (2010)
  17. 17. A Step-wise Approach 17
  18. 18. DTP #1 Patient LL requires drug therapy for the symptomatic treatment of thyrotoxicosis DTP #2 Patient LL requires drug (or non-drug) therapy for the treatment of hyperthyroidism DTP #3 Patient LL requires additional drug therapy for the rapid attainment of a euthyroid state (pretreatment) prior to thyroidectomy DTP #4 Patient LL requires reassessment of her thionamide medication due to the occurrence of adverse effects Drug Therapy Problems 18
  19. 19. Patient LL requires drug therapy for the symptomatic treatment of thyrotoxicosis Thyrotoxicosis leads to increased -adrenergic binding sites -blockers Evidence exists for the use of propranolol, atenolol, or metoprolol in the symptomatic treatment of thyrotoxicosis in patients with Graves disease Role Used to manage symptoms while hyperthyroidism is being treated with thionamides, iodine, or both +/- surgery or radioactive iodine Drug Therapy Problem #1 19 Internal Medicine (Tokyo, Japan), 51(17), 2285-2290 The American Journal of Medicine, 93(1), 61-68
  20. 20. Data Patients symptoms include tachycardia (HR 114), palpations, tremor, and anxiety Assessment In addition to PTU, -blocker indicated, effective and safe for the treatment of symptoms of thyrotoxicosis Plan Atenolol 50mg PO bid Option to increase to 100mg BID if patient is still tachycardic Symptomatic Management 20
  21. 21. 21 Patient LL requires drug (or non-drug) therapy for the treatment of hyperthyroidism Treatment options for the remission of Graves disease: 1. Thionamides (aka Antithyroid Drugs) 2. Radioactive iodine (I-131) 3. Thyroidectomy Drug Therapy Problem #2
  22. 22. 22 Methimazole is 10-15x more potent than PTU PTU blocks peripheral conversion of T4 to T3 (more so at >600mg/d) Carbimazole is the prodrug of methimazole Competitively inhibit the incorporation of iodine into T4 and T3 precursor known as thyroglobulin Do not have an effect on preformed thyroid hormone, therefore the effects are seen once T3 and T4 stores are depleted (1-6 weeks) Euthyroidism is usually achieved in 6-12 weeks Can be used as the sole treatment modality (12-24 months), as an adjuvant to radioiodine, or for the attainment of euthyroidism before surgery High relapse rate of 50-70% most often occur within 3-6 months of drug discontinuation Thionamides Farwell, A. P., & Braverman, L. E. (2006)
  23. 23. 23 Graves' Hyperthyroidism: Treatment with Antithyroid Drugs, Surgery, or Radioiodine A Prospective, Randomized Study All 3 treatments were equally effective in establishing a hypothyroid state with subsequent T4 supplementation at 12 months Radioactive iodine took a few weeks longer to achieve a hypothyroid state generally achieved in 2-6 months Rates of relapse back to hyperthyroidism: Thionamides > radioactive iodine > surgery Graves Treatment Options The Journal of Clinical Endocrinology and Metabolism, 81(8), 2986-2993
  24. 24. 24 Graves Treatment Plan Data Patient is still hyperthyroid with no signs of improvement despite 4 weeks treatment with methimazole 30mg once daily Assessment Inadequate response with 4 weeks of thionamide treatment and unlikely to respond to thionamides alone Plan Switch from methimazole to PTU Surgery (near total/ total thyroidectomy)
  25. 25. 25 Patient LL requires additional drug therapy for the rapid attainment of a euthyroid state (pretreatment) prior to thyroidectomy Surgeries include subtotal, near-total, and total thyroidectomy Bleeding, injury to the laryngeal nerve, and hypoparathyroidism are potential risks Mortality and morbidity from surgery are reduced when the metabolic state of the thyroid gland is normalized and vascularity is reduced before surgery How is this done promptly? Thionamides Inorganic Iodide Plasmapheresis? Drug Therapy Problem #3 Mandel, S. J., Larsen, P. R., & Davies, T. E. (2011)
  26. 26. 26 Oldest treatment for disorders of the thyroid Blocks thyroid hormone release, inhibits thyroid hormone synthesis (Wol