9/1/2015 Amiodarone Thyroid Toxicity 2015 Bryan Heart Conference Shannon Wakeley MD 9/5/15 Disclosures • I speak on behalf of the following companies: Astra Zeneca, Boehringer Ingelheim, Johnson & Johnson, Sanofi and Valeritas. I receive funding for clinical research from Medtronic. Endocrinologists have 2 arch enemies…. amiodarone and prednisone 1 9/1/2015 Objectives • Discuss how amiodarone affects the thyroid • Identify how to diagnose amiodarone thyroid toxicity • Differentiate between Type 1 & Type 2 AIT • Determine appropriate treatment of patients with amiodarone thyroid disease. Amiodarone • A class III anti-arrhythmic drug, with multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. • Associated with several side effects: pulmonary toxicity, hepatotoxicity, peripheral neuropathy, hyperthyroidism and hypothyroidism. Amiodarone • Contains two atoms of iodine per molecule • Each 200mg tablet contains 75mg of iodine, 10% released as free iodine daily. • WHO optimal iodine intake is 0.15-0.3mg/day • Stored in adipose tissue, myocardium, liver, lung • 40-fold increase in plasma and urinary iodine levels with long term use. • Elimination half-life of 2-3 months 2 9/1/2015 Thyroid monitoring • Assess thyroid function tests before and at 1 and 3 months following initiation of amiodarone and at 3-6 month intervals thereafter Amiodarone Induced Hypothyroidism (AIH) • AIH: due to the inability of the thyroid to escape from the Wolff-Chaikoff effect. Inhibition of thyroid hormone biosynthesis due to the block in intrathyroidal iodine organification. • 40% of patients with AIH have positive thyroid antibodies. • Incidence of AIH ranges 6-13% • Treatment: discontinue amiodarone if possible, if not, treat as if it was not amiodarone related! Case Study • 64 y/o M w/CAD s/p 3V CABG age 57, obesity, HTN, HLP, DM2. Atrial fibrillation diagnosed 1 year ago, started on amiodarone. • Pre-tx TSH=3.10, fT4 1.2ng/dL • Current TSH=0.01, fT4 3.8ng/dL (0.8-1.8) • unintentional 10# weight loss, (+) tremors, fatigue and muscle weakness • PE: goiter, firm irregular gland, no distinct nodules palpated 3 9/1/2015 What labs/studies would you order? • A. Radioactive iodine uptake scan • B. IL-6 level • C. Thyroid ultrasound • D. TSI (thyroid stimulating immunoglobulin) Amiodarone Thyrotoxicosis • AIT develops in 3% of amiodarone treated patients in North America • May occur months to years after starting therapy • May occur after discontinuing therapy • Type 1 & Type 2 AIT Type 1 • AIT Type 1: Iodine induced excessive thyroid hormone synthesis (Jod Basedow phenomenon) • Multinodular Goiter • (Latent) Graves Disease 4 9/1/2015 AIT Type 2 • AIT Type 2: Self limited destructive thyroiditis • Pre-existing normal thyroid • Painless • Auto-antibodies generally negative Differentiating between Type 1 and Type 2 AIT • Important as treatment is different • It can be difficult…. • Patients can have a mixture of both mechanisms. • Thyroid function tests are the same • Normally etiology of hyperthyroidism can be determined by radioactive iodine uptake scan… RAI uptake scan 5 9/1/2015 Type 1 vs Type 2? • Iodine -131 uptake scan typically NOT HELPFUL in iodine sufficient areas. • Many patients will have low uptake (<3%) because the uptake of radioiodine tracer is inhibited by high intrathyroidal iodine concentrations. • IF 24h RAI uptake IS detectable, it suggests Type 1 AIT • Thyroid receptor antibody (TSHRAb) or thyroid stimulating immunoglobulin (TSI): HELPFUL as suggests underlying Graves’ disease. • IL-6: normal to mildly elevated in AIT1, high in AIT2 • However, IL-6 can be elevated in patients with other coexisting illness (CHF, Graves’ disease, non-thyroidal conditions). Some pts with AIT2 have unexpectedly low levels of IL-6 due to the commercial assay used—>NOT HELPFUL Type 1 vs Type 2 • Thyroid ultrasound (sort of helpful): patients with Type 1 AIT often have multi nodular goiters or diffuse goiter, patients with Type 2 AIT usually have no goiter or a small diffuse goiter. • Color flow doppler sonography: increased blood flow is consistent with diagnosis of Type 1 AIT. • Subject to intraobserver variability. No gold standard. Requires experience sonographer • (Sestamibi thyroid scan - related to thyroid blood flow, may be option in future, pending studies) Treatment • Do you stop the amiodarone?? • It may be necessary to prevent a life-threatening arrhythmia • 1/2 life of elimination from the body is ~100 days, there is no immediate benefit to stopping amio. • Amio blocks T4 to T3 conversion, beta-adrenergic receptors and possibly T3 receptors, stopping amio might exacerbate hyperthyroid symptoms. 6 9/1/2015 Treatment • AIT Type 1: thionamides - methimazole. Higher than average doses are often required (450-600mg PTU daily or methimazole 30-40mg daily). • Dosages are gradually tapered to a low maintenance dose • If amiodarone is stopped, methimazole can be discontinued after 6-18 mos (once amiodarone is eliminated from the body) Urinary iodine levels can be measured. • Lithium used in addition to thionamides to speed recover if thyrotoxicosis is severe (>23 mos on amio, fT4 >50% above the upper limit of nl). Treatment • AIT Type 2: glucocorticoids for anti-inflammatory and membrane-stabilizing effect • Prednisone 30-40mg daily tapered over 2-3 mos. • Start with high dose for at least a month before tapering. One study of 66 pts 60% were euthyroid within one month and 16% hyperthyroid for more than 3 mos. • Frequent blood draws, adjustment of meds as needed. • Risk of recurrence ~6%, cases mild and short lived Case Study (cont’d) • Thyroid U/S: reveals 6mm nodule RUL, heterogeneous thyroid gland, blood flow not mentioned in report • TSI: negative 7 9/1/2015 How would you treat this patient? • A. 30mg methimazole po q day • B. 30mg prednisone po q day • C. Stop Amiodarone • D. A + B AIT: Uncertain if 1 or 2 • Methimazole 30-40mg/day + Prednisone 30-40mg/day • 2 weeks: get thyroid labs under control (fT4, fT3, TSH) • A rapid response suggests type 2 AIT—-> d/c methimazole, try to taper prednisone • If no significant change - continue methimazole, discontinue prednisone • **For patients who fail to respond to therapy total thyroidectomy should be considered. Often, risk of surgery (~9% mortality) under careful cardiovascular monitor is less than the risk of several months of uncontrolled hyperthyroidism. • **Plasmapheresis in case reports only. Case Study (cont’d) • Patient was treated with both methimazole 30mg daily + prednisone 30mg daily • 2 weeks later: TSH 0.01, fT4 1.9ng/mL (0.8-1.8) • Methimazole stopped and prednisone was tapered over the next 2 months. • 2 months later: TSH 2.7, fT4 1.3ng/dL • Patient most likely had AIT Type 2 8 9/1/2015 References • Bahn et al. “Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.” THYROID vol 21, No. 6, 2011 • Tsang et al. “Amiodarone-induced thyrotoxicsoes: A review.” Can J Cariol 2009 Jul; 25(7): 421-424. • Loh, Keh-Chuan. “Amiodarone-induced thyroid disorders: a clinical review.” Postgrad Med J 2000; 76:133-140 • Sato et al. “Mild and short recurrence of type II amiodarone-induced thyrotoxicosis in three patients receiving amiodarone continuously for more than 10 years.” Endocrine Journal 2006; 53:531 9.