Common Thyroid Disorders

Transcription

1 Learning Objectives Common Thyroid Disorders 1. Apply clinical practice guidelines to the diagnosis and treatment of hypothyroidism 2. Describe the modification of thyroxine replacement dose in the setting of chronic medical conditions and in pregnancy 3. Apply clinical practice guidelines to the diagnosis and treatment of hyperthyroidism 4. Describe the approach to the diagnosis and treatment of amiodarone-associated hypothyroidism and hyperthyroidism Faculty Gregory A. Brent, MD Professor, Medicine and Physiology David Geffen School of Medicine at UCLA Los Angeles, California Slides are current as of the time of printing and may differ from the live presentation due to copyright issues. Please reference for the most up-to-date version of slide sets. West Annual Conference Anaheim, California April 27-30, 2016

2 Common Thyroid Disorders Gregory A. Brent Professor of Medicine and Physiology David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Clinical Practice Guidelines for Management of Thyroid Diseases Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer-ATA-2015 Hyperthyroidism and other Causes of Thyrotoxicosis- ATA/AACE-2011 Clinical Practice Guidelines for Hypothyroidism in Adults- ATA/AACE-2012 Guidelines for the Treatment of Hypothyroidism-ATA-2014 The Use of L-T4 +L-T3 in the Treatment of Hypothyroidism- ETA-2012 Guidelines for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum-ATA-2011, Endo Soc 2012, ETA 2014, ATA-2016 ATA = American Thyroid Association; Endo Soc =The Endocrine Society; AACE = American Association of Clinical Endocrinologists; ETA = European Thyroid Association. Management of Hypothyroidism Treatments to slow down or reverse hypothyroidism, triggers to autoimmune hypothyroidism Initiation of levothyroxine Patients with complaints of weight gain or persistent symptoms, use of T4/T3 combination therapy. Patients on medications that interfere with the thyroid, such as amiodarone Levothyroxine therapy in the elderly Adjusting levothyroxine in thyroid cancer patients Levothyroxine therapy in pregnancy What causes Hashimoto's disease and can it be prevented or reversed? Underlying Risk-genetic predisposition, family history of autoimmune thyroid disease (Hashimoto's or Graves'), other autoimmune diseases Triggers-excess iodine, medical radiation, medications (lithium, interferon, amiodarone) Reversibility-Usual pathogenesis is progressive lymphocyte-mediated destruction of thyroid tissue. Only reversible is rare hypothyroidism due to transient TSH- Receptor blocking antibodies. Essential Elements: Iodine ug/day optimal, not > 600 ug/day Selenium-50 ug per day (supplementation may be needed for dialysis, HIV) Brent GA, Thyroid 20:755, Why is levothyroxine monotherapy considered to be the standard of care for hypothyroidism? Efficacy in resolving the symptoms of hypothyroidism Long-term experience of its benefits Favorable side effect profile Ease of administration Good intestinal absorption Long serum half-life (7-10 days) Low cost What is the best approach to initiating and adjusting levothyroxine therapy? Thyroid hormone therapy should be initiated as an initial full replacement, or as partial replacement with gradual increments in the dose titrated upward using serum TSH as the goal. Dose adjustments should be made when there are large changes in body weight, with aging, and with pregnancy. TSH assessment 4-6 weeks after any dosage change.

3 Indications for Thyroxine Treatment of Subclinical (mild) Hypothyroidism What are the potential deleterious effects of excessive levothyroxine? Recommend Thyroxine Treatment TSH>10 mu/l Anti-TPO+ and goiter Undergoing infertility treatment Recurrent miscarriage Pregnant Consider Thyroxine Treatment TSH 5-10 mu/l Anti-TPO+ no goiter Symptoms (eg. Persistent Fatigue) Hyperlipidemia Depression The deleterious health effects of iatrogenic thyrotoxicosis include atrial fibrillation and osteoporosis. Avoid subnormal serum TSH values, particularly TSH values below 0.1 miu/l, especially in older persons and postmenopausal women. Garber et al Clinical Practice Guidelines for Hypothyroidism in Adults-ATA/AACE- Thyroid 22:1200, 2012 Levothyroxine Formulations % Increase Dose (µg) % Decrease Difference of <25% Should levothyroxine therapy for hypothyroidism, particularly in specific sub-groups such as those with obesity, depression, dyslipidemia, or who are athyreotic, be targeted to achieve high-normal T3 levels or low-normal TSH levels? There is insufficient evidence of benefit to target low-normal TSH values or highnormal T3 values in those patients with hypothyroidism who are overweight, or those who have depression, dyslipidemia, or who are athyreotic. What should be considered when patients on thyroxine alone have persistent symptoms? Possible causes of persistent complaints in L-T4- treated hypothyroid patients: Nonspecific causes: related to the chronic nature of the disease Specific causes: related to thyroid disease and thyroid Hormone replacement Associated autoimmune diseases, consider hypoadrenalism Thyroid autoimmunity per se Inadequacy of L-T4 dose Inadequacy of L-T4 treatment modality Wiersinga WM, et al. ETA T4/T3 Guidelines Eur Thyroid J. 2012;1: In adults requiring thyroid hormone replacement treatment for primary hypothyroidism who feel unwell while taking levothyroxine, is combination treatment including levothyroxine and liothyronine superior to the use of levothyroxine alone? There is currently insufficient evidence to support the routine use of a trial of a combination of levothyroxine and liothyronine therapy outside of a formal clinical trial, due to uncertainty in long-term risk benefit ratio of the treatment. INSUFFICIENT EVIDENCE

4 Comparison of Levothyroxine and Desiccated Thyroid Extract (DTE) Measures Daily Dose Weight (lb) Total T3 ( ng/dl) Free T4 ( ng/dl) TSH (0.27-4,20 uiu/ml) SHBG ( nmol/l) DTE Treatment (N=70) ± 30 mg (43-172) Hoang, et al. J Clin Endocrinol Metab. 2013;98:1982. L-T4 Treatment (N=70) 119 ± 39 ug (75-225) P Value ± ± 38 < ± ± ± ± ± 0.77 (0.54 to 3.0) 1.30 ± 0.63 ( ) < < No difference in HR, BP, neuropsychological measures, total cholesterol, LDL, HDL, Triglycerides Comparison of Levothyroxine and Desiccated Thyroid Extract (DTE) 34 patients (49%) preferred DTE 13 patients (19%) preferred L-T4 23 patients (32.9%) had no preference The subset that preferred DTE lost 4 lb, subjective symptoms improved, improved general health and thyroid symptom questionnaire. Average DTE dose 80 mg (provided as 15, 30, 60, 90, 120 mg) Average levothyroxine dose 120 ug Hoang, et al. J Clin Endocrinol Metab. 2013;98:1982. How should T4/T3 combination therapy be used to treat hypothyroidism? It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Example: If a patient is on 100 ug levothyroxine and well controlled, 95ug L-T4/5 ug L-T3, would be 19:1 Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Agents and Conditions Having an Impact on L- thyroxine Therapy and Interpretation of Thyroid Tests Interference with Absorption: Bile acid sequestrants (cholestyramine, colestipol, colesevelam) Sucralfate Cation exchange resins (Kayexelate) Oral biophosphonates Proton pump inhibitors Raloxifene Multivitamins (containing ferrous sulfate or calcium carbonate) Ferrous sulfate Phosphate binders (sevelamer, aluminum hydroxide Calcium salts (carbonate, citrate, acetate) Chromium picolinate Charcoal Orlistat Ciprofloxacin H2 receptor antagonists a Malabsorbtion syndromes Celiac disease Jejunoileal bypass surgery Cirrhosis (biliary) Achlorhydria Diet Ingestion with a meal Grapefruit juice a Espresso coffee High fiber diet Soybean formula (infants) Soy Wiersinga WM, et al. ETA T4/T3 Guidelines Eur Thyroid J. 2012;1: ATA/AACE Guidelines for Hypothyroidism. Garber JR, et al. Thyroid. 2012;22: Amiodarone and Hypothyroidism 75 mg iodine/200 mg tablet of aminodarone Transient increase in TSH in first 1-3 months of therapy Increased risk of hypothyroidism with positive anti-tpo antibodies TSH measured beyond 4 months of therapy: If TSH elevated but <10mIU/L, normal FT4, no signs of symptoms, repeat in 3-6 months If TSH >10 miu/l, treat with levothyroxine, begin with low dose, ug per day Kahaly et al Dtsch Arztebl 104: A 3550, 2007 How should levothyroxine therapy be managed in the elderly with hypothyroidism? Levothyroxine should be initiated with low doses, and the dose titrated slowly based on serum TSH measurements. Normal serum TSH ranges are higher in older populations (such as those over 65 years), and higher serum TSH targets may be appropriate for those on thyroxine replacement.

5 Age Distribution of TSH from NHANES III Survey Data Percent (%) Percent (%) Upper TSH Concentration in Bin Surks and Hallowell. J Clin Endocrinol Metab. 2007;92: Disease Free No report of thyroid disease or meds Age Age Age 80+ Reference Population No pregnancy, thyroid antibodies, related med What is the appropriate degree of TSH suppression in patients with Differentiated Thyroid Cancer? For high-risk thyroid cancer patients, initial TSH suppression to below 0.1 mu/l is recommended. For intermediate-risk thyroid cancer patients, initial TSH suppression to mu/l is recommended. For low-risk patients who have undergone remnant ablation and have undetectable serum Tg levels, TSH may be maintained at the lower end of the reference range (0.5 2mU/L) while continuing surveillance for recurrence. Similar recommendations hold for low-risk patients who have not undergone remnant ablation and have undetectable serum Tg levels. Haugen et al Thyroid 26:1, 2016 How should levothyroxine therapy be managed in pregnant women with hypothyroidism? Titrate levothyroxine replacement to achieve a TSH concentration within the trimester-specific reference range. Serial serum TSH levels should be assessed every four weeks during the first half of pregnancy. Serum TSH should also be re-assessed during the second half of pregnancy. For women already taking levothyroxine, two additional doses per week of the current levothyroxine dose, given as one extra dose twice weekly with several days separation, may be started as soon as pregnancy is confirmed. Endocrine Society: Management of Thyroid Dysfunction during Pregnancy and Postpartum Preexisting hypothyroidism-titrate thyroxine to maintain a serum TSH < 2.5 miu/l before pregnancy, follow-up thyroid studies at 4-6 weeks gestation. Hypothyroidism diagnosed during pregnancy, target TSH<2.5 miu/l (1st trimester), TSH < 3.0 miu/l 2nd and 3rd trimester Thyroxine increment based on initial TSH: TSH 5-10 miu/l, ug/d TSH miu/l, ug/d TSH>20 miu/l, ug/d Jonklaas J et al Guidelines for the Treatment of Hypothyroidism Thyroid 24:1670, 2014 Abalovich et al JCEM 92:S1, 2007 Management of Hyperthyroidism Evaluation of hyperthyroidism Managing medical treatment of hyperthyroidism Subclinical hyperthyroidism in the elderly Hyperthyroidism and amiodarone When should a thyroid uptake and scan be performed in a patient with thyrotoxicosis? A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of Graves Disease A thyroid scan should be added in the presence of thyroid nodularity.

6 Which patients with thyrotoxicosis should receive beta-adrenergic blockers? Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease. Beta-Adrenergic Receptor Blockade Drug Dosage Frequency Considerations Propanolol 10-40mg TID-QID Nonselective beta-adrenergic receptor blockade Longest experience May block T4 to T3 conversion at high doses Preferred agent for nursing mothers Atenolol mg QD or BID Relative beta1 selectivity Increased compliance Metoprolol 25-50mg QID Esmolol mg QD Nonselective beta-adrenergic receptor blockade, once daily Least experience to date May block T4 to T3 conversion at high doses In intensive care unit setting of severe thyrotoxicosis or storm Which antithyroid drug should be used and how should treatment be initiated? Obtain baseline complete blood count, including white count with differential, and a liver profile. Methimazole should be used except during the first trimester of pregnancy, when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery. Patients should be informed of side effects of antithyroid drugs and the necessity of informing the physician promptly if they should develop. How long should Graves disease patients be treated with antithyroid drugs and how should they be monitored? A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medication. Routine monitoring of white blood counts is not recommended. Methimazole should be continued for approximately months, then tapered or discontinued if the TSH is normal. HIGH-QUALITY EVIDENCE If a patient with GD becomes hyperthyroid after completing a course of methimazole, consideration should be given to treatment with radioactive iodine or thyroidectomy. Monitoring Response to Antithyroid Drug Therapy T4 and T3 levels begin to reduce after 2-6 weeks of therapy Reduction in heart rate and increase in body weight are typically seen in the 4-8 week range. TSH often remains suppressed even when T4/T3 are normal or even reduced. When T4/T3 are normalized, only 20% of patients have a normal range TSH. After 3 months of a normal T4/T3, 80% of patients have a normal range TSH. ATA/AACE Guidelines for Treatment of Subclinical Hyperthyroidism (suppressed TSH, normal T4/T3) Factor TSH (<0.1 mu/l) TSH ( mu/l) Age >65 Yes Consider treating Age <65 with Comorbidities Heart Disease Yes Consider treating Osteoporosis Yes No Menopausal Consider treating Consider treating Hyperthyroid Symptoms Yes Consider treating Age <65, Asymptomatic Consider treating No Chung et al Thyroid 16:1251, 2006 Bahn, et al. Thyroid. 2011;21:598.

7 Drug-Associated Thyrotoxicosis Drug Mechanism Timing Treatment Amiodarone-Type 1 Iodine induced Months to Years Supportive care Amiodarone-Type 2 Thyroiditis Often> 1 year Lithium Interferon Alpha Painless thyroiditis, GD Painless thyroiditis, GD Often> 1 year Months Interleukin-2 Painless thyroiditis Months Iodinated Contrast Radioactive Iodine Early Radioactive Iodine for Toxic Goiter Late Bahn, et al. Thyroid. 2011;21:598. Underlying thyroid autonomy Destruction GD Weeks to months 1-4 weeks 3-6 months Antithyroid drugs; perchlorate Surgery corticosteroids, surgery Antithyroid Drugs Antithyroid Drugs and or RAI (GD only) Antithyroid Drugs and/or RAI (GD only) Antithyroid drugs Observation; if severe, administer glucocorticoids Antithyroid drugs, repeat RAI, Surgery Amiodarone-Associated Hyperthyroidism 61 yo with paroxysmal atrial fibrillation, on amiodarone for 2 years, TSH 0.01 ( uiu/ml), Free T ( ng/dl), TSH Receptor Ab 4.45 U/L (positive > 1.5) How long does it take for amiodarone to influence thyroid function? Reduced T4 to T3 conversion is seen in weeks, hypothyroidism or hyperthyroidism can occur at any time during treatment. What are the types of amiodarone-associated hyperthyroidism and how are they diagnosed? Type 1 is usually with preexisting multinodular goiter or Graves' disease with increased blood flow by doppler Type 2 is destructive, previously normal thyroid, elevated IL6, non immune. How is amiodarone-associated thyroid disease treated? Type 1 is usually treated with antithyroid drugs, but can be quite resistant, sometimes addition of perchlorate or surgery is needed. Type 2 is treated with glucocorticoids to reduce inflammation. Cardiac outcomes are improved in patients treated for amiodaroneassociated hyperthyroidism. Features of Amiodarone-Induced Hyperthyroidism (AIH) Characteristics Type 1 AIH Type 2 AIH Pre Existing thyroid disease Common No Diffuse/nodular goiter Common No Onset Early (weeks) Late (months) Mechanism Production increased Release Color Doppler sonography Blood flow increased Blood flow decreased Tc uptake (thyroid scan) Unchanged Lowered Serum interleukin 6 levels Unchanged Slightly increased Thyroid antibodies Increased Normal to elevated Course Severe Mild to severe Histology Inflammatory Destructive Discontinuation of amiodarone Yes No Response to therapy Poor Good Definitive therapy necessary Yes No Transition to hypothyroidism No Possible Kahaly et al Dtsch Arztebl 2007; 104: A Evidenced-Based Recommendations for Type I and Type II Amiodarone-Induced Hyperthyroidism-Diagnosis Color Doppler Sonography Interleukin 6 (serum) Thyroid Antibodies (serum) Evidence Grade 1a Strong 2a Moderate 3a Expert Opinion Recommendation A Highly C Neutral B Recommend Tc Uptake (scan) 3b Expert Opinion C Neutral Thyroglobulin (serum) Kahaly et al Dtsch Arztebl 2007; 104: A Case Reports Only D Do Not Recommend