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CORE TOPIC: Hashimoto’s Thyroiditis & GRAVES DISEASE Megha Poddar PGY 5 Objectives • Review basic Thyroid Physiology and function • Review thyroid autoimmunity and thyroid antibodies • Review the clinical presentation, diagnosis, management of Hashimoto’s thyroiditis using the ATA Guidelines • Review the clinical presentation, diagnosis, management of Graves Disease using the ATA Guidelines and CMAJ reviews Thyroid Physiology • Thyroid gland secretes mainly T4 • 20% of hormone secreted is T3 • Remainder of T3 converted in the peripheral tissue from T4 • T3 is more biologically active in tissue • Free hormones bind to TH receptors and initiate various physiological and biochemical responses Thyroid Hormone • T4 and T3 are poorly water soluble • 99% of circulating T4 and T3 is bound to: • Thyroid binding globulin • Transthyretin • Albumin • TBG has a higher affinity for T4 and T3 • 10-20% of circulating T3 comes from direct secretion by the thyroid gland • 80-90% is produced by peripheral conversion of T4 T3 • 5’-deiodination of T4 occurs in the liver, kidney and skeletal muscle • D1 is the most abundant deiodinase and is the major converter of T4 to T3 Thyroid Hormone Function • • • • Cardiovascular: ↓ peripheral vascular resistance (PVR) and ↑ intravascular volume ↑ cardiac output ↑ rate of myocardial diastolic relaxation ↑ rate of depolarization and repolarization of the SA node (↑ heart rate) Heightened adrenergic response (↑ alpha receptors) Thyroid Hormone Function • Pulmonary • Thyroid hormone maintains ventilatory response to hypoxia and hypocapnia in the brain stem respiratory centre • Gastrointestinal • ↑ gut motility • ↑ protein turnover • Bone • ↑ bone turnover (resorption > formation) • Cholesterol • ↑ cholesterol synthesis and degradation Thyroid Autoimmunity • Macrophages ingest foreign material and present peptide fragments to the cell surface • This complex is recognized by T cell receptors on CD4 helper cells with stimulate the release of IL2 and cytokines and stimulates B-cells to make antibodies. • The CD8 suppressor is the regulator of this activity • The thyroid cells have the ability to ingest antigens and when stimulated by cytokines express cell surface molecules to present to T lymphocytes Thyroid Auto-antigens • Thyroglobulin • Thyroid Peroxidase • TSH receptor Autoimmune Hypothesis • Stimulated by external antigens that leads to antibody and immune cross reactivity • Genetics clearly predispose to autoimmunity (HLA subtypes) • ex in Caucasians goitrous Hashimotos is associated with HLA DR5 • Genetically induced issue antigen specific defect in suppressor T lymphocytes • Particularly susceptible to: • excessive iodine - kelp, amiodarone, seaweed, contrast • meds that alter immunity: interferon alpha • inability to escape from the Wolff-Chaikoff effect Autoimmunity Hypothyroidism - Epidemiology • Common! • Subclinical or Overt – TSH >10 with a subnormal T4 • Framingham data: • 5.9% of women, 2.3% of men over the age of 60 had TSH >10 • 39% of them had subnormal T4 levels Etiology of Hypothyroidism • Most common cause in iodine sufficient areas: Autoimmune thyroiditis • Removal of gland • Surgical • RAI ablation • Medications • Lithium • Amiodarone • Anticonvulsants • Iodine deprived areas (most common cause wordwide) • Secondary/Central Hypothyroidism (5%) • Hypopituitarism • Hypothalamic disorders Epidemiology: Hashimoto’s Thyroiditis • 5-10 times more common in women than in men • Increases in frequency with age • More common with if have other autoimmune disease • More common in those with a family history • Goitre may or may not be present • Can be associated with thyroid lymphoma Associations • Other autoimmune diseases: • Type 1 DM, Addisons, Celiacs disease, pernicious anemia • But don’t forget!: myasthenia gravis, SLE, RA • Rare: Thyroid Lymphoma • Genetic syndromes: • Multiple autoimmune endocrinopathies • Type 1 (AIRE – autoimmune regulator gene): Hypoparathyroidism, Addisons, mucocutaneous candidiases. 10-15% have hypothyroidism. • Type 2 (Schmidts Syndrome): Addisions, type 1 DM, autoimmune thyroiditis Signs of Hypothyroidism Findings Hypothyroidism General Vitals Lethargic and slow HR: bradycardia BP: narrow pulse pressure (↑ DSP) Temp: hypothermic Hands Cool, rough skin, yellow discolouration (carotene) H&N Hair: coarse, thick Eyes: Periorbital edema Loss of lateral 1/3 eyebrows (Queen Anne’s sign) Mouth Macroglossia Skin CVS Vitiligo, non-pitting edema Pericardial effusion, diastolic hypertension Resp CNS Pleural effusions Proximal muscle weakness, Reflexes = delayed relaxation, carpal tunnel syndrome Histology • Extensive lymphocytic infiltration with T cells and plasma • • • • cells Atrophic follicles with Hürthle cells Fibrosis but does not extend beyond capsule Epithelium may have enlarged or overlapping nuclei with partial nuclear clearing Initial lesion is focal, then oxyphilic metaplasia of follicular cells and nodularity; later little thyroid parenchyma is present Diagnosis of Hashimotos • TSH is the primary screening modality • Elevated antibody titres • Anti TG antibodies • Anti microsomal/anti-thyroid peroxidase ab, TPOAb • TSH recepter ab • Once present, ab rarely disappear spontaneously • Many patients are biochemically euthyroid • The presence of TPOab in subclinical hypothyroidism predicts progression to overt hypothyrodism • 4.3% with positive antibodies • 2.6% with negative antibodies When should you order antibodies? • Subclinical hypothyroidism – predicts future risk • Any patient with a goitre • Other autoimmune diseases, chromosomal abnormalities (Down’s), lithium, interferon alpha, amiodarone – helps determine prognosis • In pregnant women who are hypothyroid with a history of Graves’ – determines risk of neonatal thyrotoxicosis (TSHrab) Pitfalls with using TSH as screening • May be some diurnal variation – lowest in the late afternoon and highest in the first hour of sleep • NHANES III reference population was further analyzed (97.5th percentile) • TSH values as low as 3.24 for African Americans between the ages of 30 and 39 years • 7.84 for Mexican Americans ≥80 years of age. • For every 10-year age increase after 30-39 years, serum TSH increases by 0.3 mIU/L. Pitfalls with using TSH as screening • TSH may be abnormal in hospitalized patients or recovering • • • • patients, pregnancy, those on steroids or others interfering medications Patients with central hypothyroidism can still have mildly elevated TSH levels if they have bioinactive forms of TSH TSH may be elevated in patients with thyroid hormone resistance Assay interference: heterophile/interfering antibody Adrenal insufficiency will have elevated TSH which normalize follow glucocorticoid treatment ALWAYS DRAW FREE HORMONE LEVELS BEFORE STARTING TREATMENT! Treatment • Levothyroxine • Dose: based on age, sex, weight • Approximately 1.6mcg/kg • Post Op/RAI ablation/subclinical hypothyroid or Graves’ patients will likely require less • If patients has CAD – the dose is started at 12.5-25mcg less then the usual starting dose • 50-60 years old – start at 50mcg • Synthroid vs Eltroxin – doesn’t matter! • Various tablets have different formulations and bioequivalence • ATA suggests: encourage the use of a consistent L-thyroxine replacement • Ideally take 4 hours after last meal or 60min before breakfast • Should not be taken with other medications that interfere with absorption Whats the deal with triiodothyronine/T3? • Randomized, double-blind crossover intervention study done • • • • comparing T3 monotherapy with T4,14 patients for 6 weeks Comparable TSH levels were achieved. Mild weight loss and decreases in total cholesterol, LDL cholesterol, and apolipoprotein levels were seen without differences in cardiovascular function, insulin sensitivity, or quality of life with T3 compared with T4 Dose: used TID dosing for both groups ATA - not enough evidence to support its use Dose Adjustments • Repeat TSH q4-8weeks with initiation and dose adjustment • Once stable can check 6 to 12 months • Check TSH for dose adjustments if: • Pregnant • With change in medications that effect binding proteins absorption • With significant weight changes • With elderly patients GRAVES’ THYROTOXICOSIS Definition&Epidemiology • “thyrotoxicosis” refers to a clinical state that results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels. (ATA Guidelines, 2011) • Graves Disease: autoimmune disorder TRAb (thyrotropin receptor antibodies) stimulate the TSH receptor to produce thyroid hormone • Remission occurs in approx 30% of those who are not treated Symptoms • Elderly patients may present with atypical symptoms Findings associated with Graves’ • Diffuse goitre • Thyroid bruit • Thyroid acropachy (clubbing) • Lymphodenopathy (rare) • Localized dermopathy (rare) • Opthalmopathy Pathogenesis of Opthalmopathy • It initiates cytokine which activates glycosaminoglycans • Increases osmotic pressure • Extraocular muscle volume • Fluid accumulation • Clinical opthalmopathy • 50% do not have clinically evident eye findings at diagnosis • Rare (<10%) can have eye disease with normal TFT’s, however, patients will likely become hyperthyroid within 18 months • Rendering patients euthyroid often improves opthalmopathy Complications • Inability to close the eye = corneal ulceration/visual loss • Proptosis/EOM = diplopia • Optic nerve compression = colour vision disruption/visual loss Dermopathy (Pretibial myxedema) Nonpitting edema with occasional raised, hyperpigmented, violaceous papules. • Patients often have high titres of TSH receptor antibodies • Trauma may initiate or exacerbate • 10% will have a increased free T3 with a normal free T4 • Confirmation is with RAIU • If a cold nodule is present it should be confirmed with an ultrasound +/- biopsy Treatment Treatment Modalities - ATD Why Pick ATD • High likelihood of remission • Limited life expectancy/High surgical risk • Moderate to severe active GO • Previous irradiated /operated neck Contraindications •Adverse reactions to previous ATD •Baseline low neutrophil count (<0.5), transaminase >5x ULN Impact on Patient Preference If remits – eliminates need for lifelong thyroid hormone replacement • Avoid surgery/exposure to radiation • Continued monitoring for side effects and disease reoccurrence • Treatment Modalities – I131 Why Pick I131 • Females planning pregnancy after 6-12 months • Comorbidities that increase surgical risk • Contraindication to ATD use/no surgeon available in area Contraindications • • • • Pregnancy/Lactation Thyroid Cancer/Suspicion for Cancer Unable to comply with radiation safety guidelines Planning pregnancy in next 4-6 months Patient Preference • • • • Higher chance of definitive control Avoids surgery Rapid resolution Can worsen GO Treatment Modalities - Surgery Why Pick Surgery • • • • • Symptomatic compression (>80g) Low uptake of iodine Suspicion for malignancy Moderate-severe active GO Females planning pregnancy in less than 4-6 months (esp if TRab high) • Co –existing hyperparathyroidism requiring surgery Contraindications • • Substantial comorbidities Pregnancy *relative – late-second trimester Patient Preference Impact • • • • Rapid and definitive control Avoidance of radiation exposure Need lifelong thyroid replacement Invasive treatment modality ATD • Methimazole has better side effects profile • Use PTU in first trimester of pregnancy, if do not have private drug coverage • Inform patients of Side Effects • Rash • Agranulocytosis: fever, pharyngitis • Hepatic Injury: Jaundice, pale stools/dark urine, arthralgia, abdominal pain • Need baseline: CBC, LFT’s, Bilirubin • Aplasia Cutis in babies • PTU: ANCA small vessel vasculitis • CBC if fever/pharyngitis – not routinely • Taper after 12-18 months if TSH is normal, recheck TRab I131 • Complications • GO • Thyroid Storm • Rare • Pretreat 1) elderly 2) comorbidities intolerable to hyperthyroid symptoms 3) Free T4 2-3x Normal or highly symptomatic • Pretreat with Bblocker +/- ATD • Pregnancy test for all females of childbearing age 48 hours before • Most patients respond within 4-8 weeks – required 4-6 repeat monitoring • If still hyperthyroid after 6 months – need retreatment with radiation 38.7 vs 21.3% J Clin Endocrinol Metab. 2009 Oct;94(10):3700-7. doi: 10.1210/jc.2009-0747. Epub 2009 Sep 1. Steroids for GO • Prednisone, 0.5 mg/kg, start day after radioiodine for 1 month then taper over the next 3 months could prevent radioiodine-induced worsening of ophthalmopathy. • Suggested: reserve steroids only for patients with significant diplopia or proptosis, active eye disease • Reduce the risk: • ensuring stability of ophthalmopathy for 6 months before radioiodine • pretreatment with antithyroid drugs • smoking cessation • Use ablative doses of radioiodine • ? Starting L-thyroxine when patient is euthyroid References 1. 2. 3. 4. 5. 6. 7. CMAJ March 4, 2003 vol. 168 no. 5 Review, Diagnosis and management of Graves' disease, Jody Ginsberg ATA/AACE Guidelines HYPERTHYROIDISM AND OTHER CAUSES OF THYROTOXICOSIS: MANAGEMENT GUIDELINES OF THE AMERICAN THYROID ASSOCIATION AND AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS Rebecca S. Bahn ATA/AACE Guidelines CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS: COSPONSORED BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN THYROID ASSOCIATION Jeffrey R. Garber UptoDate Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind, Crossover Trial of Liothyronine Versus Levothyroxine Francesco S. Celi http://www.pathpedia.com/education/eatlas/histopathology/thyroid_gland/hashimoto_thyroiditis.as px Thyroid-Associated Ophthalmopathy after Treatment for Graves’ Hyperthyroidism with Antithyroid Drugs or Iodine-131Frank Träisk,